阅读说明：本技术 吡喃并联吡啶化合物的晶体 (The crystal of pyrans and Bipyridine compound ) 是由 栉田郁雄 伊藤洋子 松田将明 于 2018-05-07 设计创作，主要内容包括：本发明提供由式(I)表示的化合物的晶体,其可用作药物的原料药。<Image he="442" wi="557" file="DDA0002228449740000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides the crystal by formula (I) compound indicated, can be used as the bulk pharmaceutical chemicals of drug.)

1. the fluoro- 6- of 2- (fluoro- 8- oxo -7- (the pyridin-3-yl) -7,8- dihydro -6H- pyrans of the 3- simultaneously [3,2- indicated by formula (I) B:5,4-b '] bipyridyl -9- base) benzonitrile a kind of crystal

[chemical formula 1]

2. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 1 type crystal, in powder In last X-ray diffraction, the crystal has diffraction maximum at 10.8 ° of the angle of diffraction (2 θ ± 0.2 °).

3. crystal according to claim 2, wherein in powder x-ray diffraction, the crystal at 10.2 °, 10.8 ° and There is diffraction maximum at 30.4 ° of the angle of diffraction (2 θ ± 0.2 °).

4. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 1 type crystal, In¹³C In solid state NMR spectroscopy, the crystal is in 65.8ppm, 107.2ppm, 113.4ppm, 126.4ppm, 145.1ppm and 160.1ppm Chemical shift (δ ± 0.5ppm) at have peak value.

5. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 1 type crystal, it is described Crystal has x-ray diffractogram of powder shown in FIG. 1.

6. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 3 type crystal, in powder In last X-ray diffraction, the crystal has diffraction maximum at 24.4 ° of the angle of diffraction (2 θ ± 0.2 °).

7. crystal according to claim 6, wherein in powder x-ray diffraction, the crystal at 15.8 °, 18.4 ° and There is diffraction maximum at 24.4 ° of the angle of diffraction (2 θ ± 0.2 °).

8. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 3 type crystal, In¹³C In solid state NMR spectroscopy, the crystal 64.3ppm, 110.4ppm, 122.7ppm and 127.1ppm chemical shift (δ ± 0.5ppm) place has peak value.

9. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 3 type crystal, it is described Crystal has x-ray diffractogram of powder shown in Fig. 3.

10. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile hydrate crystal, in powder X-ray In x ray diffraction, the crystal has diffraction maximum at 5.5 ° of the angle of diffraction (2 θ ± 0.2 °).

11. crystal according to claim 10, wherein in powder x-ray diffraction, the crystal at 5.5 °, 14.0 ° and There is diffraction maximum at 27.2 ° of the angle of diffraction (2 θ ± 0.2 °).

12. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile hydrate crystal, In¹³C solid-state In NMR spectra, the crystal in 63.7ppm, 100.4ppm, 109.6ppm, 117.2ppm, 129.1ppm, 147.3ppm and There is peak value at the chemical shift (δ ± 0.5ppm) of 156.3ppm.

13. crystal according to claim 1, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile hydrate crystal, the crystal With x-ray diffractogram of powder shown in fig. 5.

14. a kind of pharmaceutical composition, described pharmaceutical composition is made comprising crystal according to any one of claim 1 to 13 For active constituent.

Technical field

The present invention relates to the pyrroles with alpha-amido -3- hydroxy-5-methyl base -4- isoxazole propionic acid (AMPA) receptor inhibiting effect Mutter and Bipyridine compound crystal.

Background technique

It is well known that important from the glutamic acid that cynapse proparea discharges is in the excitatory signal conduction of central nervous system Effect.When glutamic acid is in conjunction with the glutamate receptor in cynapse back zone, this effect can be generated.Glutamate receptor can be divided into from Subtype receptor and g protein coupled receptor, the former can be further divided into alpha-amido -3- hydroxy-5-methyl base -4- isoxazole propionic acid (AMPA) receptor, N-methyl-D-aspartate (NMDA) receptor, kainic acid receptor etc..Wherein, ampa receptor is wide in brain The receptor of general expression, and play a crucial role in the transmitting of Quick-type excitatory synapse or the adjusting of synaptic plasticity.

Therefore, because important function of the ampa receptor in physiology, it is known that its dysfunction will lead to a variety of diseases, example Such as, cause the neuron exaltation there are the ampa receptor.The example of such disease includes epilepsy, various pain (surroundings Nerve pain, nervous centralis pain and nociceptive pain (respectively including chronic, acute or intermittent pain)), various demyelinates Disease such as multiple sclerosis, various neurodegenerative diseases such as Parkinson's disease, Alzheimer disease, amyotrophic lateral sclerosis (ALS), Huntington chorea and AIDS (AIDS) neuropathy, various mental diseases, as anxiety, depression, two-phase emotional handicap, according to Rely, drug abuse and schizophrenia, dyskinesia such as cerebral ischemia, head injury, cerebral spinal cord injury, are trembled, Muscle tensility The developmental disorders such as obstacle and dyskinesia and self-closing disease.Therefore, the inhibitor (AMPA inhibitor) of ampa receptor is expected to treat These diseases, especially known its can be used for treating epilepsy (non-patent literature 1).

Epilepsy is one of most common central nervous diseases, and there are about 50,000,000 or more epileptics in the whole world.According to The definition of the World Health Organization, epilepsy are " the chronic brain diseases as caused by many reasons；It is mainly shown as brain neuron mistake Recurrent outbreaks (epileptic attack) caused by degree discharges, the clinic and inspection result of epileptic attack are widely different ".

The example of known epileptic attack includes partial seizures, such as simple partial seizure, complex partial seizures With secondary generalized seizures, absence seizure, myoclonic breaking-out, Myoclonic seizures, tonic seizures, tonic-clonic hair Make, lose tension breaking-out, tuberous sclerosis complication, De Lawei (Dravet) syndrome, progressive myoclonus epilepsy, La Fu Draw disease, father-in-law's Wei Richter-Lundberg (Unverricht-Lundborg) disease, repeats of dentatorubropallidolatrophy atrophy disease, Fragile X syndrome, West (West) syndrome and thunder Knox-Goss support (Lennox-Gastaut) syndrome. Drug therapy of the epilepsy therapy based on antiepileptic.The target of epilepsy therapy is to eliminate epileptic attack, and treatment is avoided to cause Side effect.In principle, it is treated since using single medicine using antiepileptic.In general, single therapy successively makes With two or three of different drug, if it fails, then attempting a variety of drug therapies.In new hair epileptic, about 70% Patient is expected to improve epileptic attack by using Antiepileptic Drugs.It is well known, however, that in remaining about 30% patient, i.e., Use the drug therapy including polypharmacy, it is also difficult to inhibit epileptic attack.

It is believed that the exaltation when some neurons develops into the abnormal synchronous discharge in entire neuronal populations When, epileptic attack can be caused, and there are many reports to claim glutamate neuron (especially ampa receptor) in epileptic attack Occur and plays a crucial role in spreading.For example, it was reported that AMPA inhibitor can inhibit the convulsions mould of rat Bic induction The generation and diffusion (non-patent literature 2 and 3) fainted from fear in type；Additionally, it is well known that AMPA inhibitor is in numerous convulsion models Show effective anticonvulsant action (non-patent literature 4 and 5).Furthermore it is known that AMPA inhibitor is extremely serious in experience and connects Also have the function of stopping epilepsy in the status epilepticus model that supervention is made, therefore, AMPA inhibitor is also expected to be used for epilepsy Persistent state (non-patent literature 6).

It is reported that similar to the mankind, from the sample that epileptic obtains, the expression of ampa receptor is containing epileptic focus Hippocampal neuron in increase (non-patent literature 7).Shy further, since having reported ampa receptor inhibitor in human body and having had to resist The effect of fainting, therefore they are expected to effect (non-patent literature 5) as the medicament of especially treatment epilepsy.

As described above, AMPA inhibitor is expected to the therapeutic agent as a variety of central nervous diseases such as epilepsy；It is well known, however, that They show the dosage of main effect central nervous system impression are caused to act on to be essentially equal to or lower than, such as calm or lose Coordinate (non-patent literature 8).It is reported that, if dosage gradually increases, the inhibiting effect of central nervous system can drop in the mankind Low (non-patent literature 9)；However, the inhibiting effect of central nervous system can be observed under high dose in, this is to needing to grow The problem of epileptic of phase administration causes quality of life to decline, and lead to the limitation of dosage.

Known following compounds are the compounds (patent document 1) with ampa receptor inhibiting effect:

[chemical formula 1]

Wherein A¹、A²And A³C6-14 aromatic hydrocarbons cyclic group or 5 yuan can be each independently to 14 membered aromatic heterocycle groups； X¹、X²And X³Singly-bound can be each independently；Q can be oxygen atom；Z can be carbon atom；R¹And R²It can be connected with each other, so that CR²-ZR¹Form the carbon-to-carbon double bond indicated by C=C；R³It can be with A³On any atom connection, and with the atom one It rises, optionally replace 5 yuan can be formed to 8 circle heterocyclic rings.

Particularly, the example 9 of patent document 1 discloses the compound with three ring skeletons being expressed from the next:

[chemical formula 2]

Cited literature 2 inventory

Patent document

[patent document 1] WO 02/22587

Non-patent literature

[non-patent literature 1] Daniela Catarzi et al., Medicinal Research Reviews [medical research Comment], volume 27, the 2nd phase, the 239-278 pages, 2007

[non-patent literature 2] Rogawski MA et al., Acta Neurol Scand Suppl. [Scandinavia mind Through journal], 2013；(197): 9-18

[non-patent literature 3] Alfonso Tortorella et al., JPET [pharmacology and experimental therapy magazine], 280: 1401-1405,1997

[non-patent literature 4] De Sarro et al., Curr Top Med Chem. [the current proposition of medical chemistry], 2005；5 (1): 31-42

[investigation drug expert comments [non-patent literature 5] Russo E et al., Expert Opin Investig Drugs By] .2012 September；21 (9): 1371-89

[non-patent literature 6] Brita Fritsch et al., Epilepsia [epilepsy], 51 (1): 108-117,2010

[non-patent literature 7] Hosford DA et al., J Neurosci [Journal of Neuroscience] 1991；11:428-434

[non-patent literature 8] Shun-ichi Yamaguchi et al., Epilepsy Research [epilepsy research], 15 (1993)179-184

[non-patent literature 9] Hanada T.Expert Opin Drug Discov [drug discovery expert opinion] .2014 24 days 2 months year, 9 (4): 449-458

Summary of the invention

Technical problem

Compound (the fluoro- 6- of 2- (fluoro- 8- oxo -7- (pyridin-3-yl) -7, the 8- dihydro-of 3- indicated by following formula (I) 6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile, it is also referred to as " compound (I) " hereinafter) have as treatment The potential use of antiepileptic drugs with ampa receptor inhibiting effect, and reduces central nervous system impression effect.

[chemical formula 3]

In general, the physical property of compound and the crystal as drug is to drug bioavailability, bulk pharmaceutical chemicals purity, drug The tools such as dosage form have a significant impact.Therefore, the purpose of the present invention is to provide the crystal of compound (I).

Solution to problem

In view of the foregoing, the present inventor conducts extensive research compound (I), and as a result inventor has found chemical combination The crystal of object (I), and complete the present invention.

In short, the present invention relates to following<1>to<18>.

<1>by the fluoro- 6- of 2- of formula (I) expression, (the fluoro- 8- oxo -7- (pyridin-3-yl) of 3- -7,8- dihydro -6H- pyrans is simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile a kind of crystal:

[chemical formula 4]

<2>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl)-of 3- 7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 1 type crystal (i.e. " and 1 type without Water object crystal "), in powder x-ray diffraction, the crystal has diffraction maximum at 10.8 ° of the angle of diffraction (2 θ ± 0.2 °).

<3>crystal according to<2>, wherein in powder x-ray diffraction, the crystal at 10.2 °, 10.8 ° and There is diffraction maximum at 30.4 ° of the angle of diffraction (2 θ ± 0.2 °).

<3.1>crystal according to<2>, wherein in powder x-ray diffraction, the crystal 10.2 °, 10.8, 16.8, there is diffraction maximum at 26.2 ° and 30.4 ° of the angle of diffraction (2 θ ± 0.2 °).

<3.2>crystal according to<2>, wherein in powder x-ray diffraction, the crystal 10.2 °, 10.8 °, There is diffraction at 16.8 °, 18.7 °, 23.4 °, 24.9 °, 26.2 °, 27.1 °, 28.1 ° and 30.4 ° of the angle of diffraction (2 θ ± 0.2 °) Peak.

<4>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl)-of 3- 7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 1 type crystal, In¹³C solid-state In NMR spectra, change of the crystal in 65.8ppm, 107.2ppm, 113.4ppm, 126.4ppm, 145.1ppm and 160.1ppm There is peak value at displacement study (δ ± 0.5ppm).

<5>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl)-of 3- 7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 1 type crystal, the crystal With x-ray diffractogram of powder shown in FIG. 1.

<6>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl)-of 3- 7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 3 type crystal (i.e. " and 3 types without Water object crystal "), in powder x-ray diffraction, the crystal has diffraction maximum at 24.4 ° of the angle of diffraction (2 θ ± 0.2 °).

<7>crystal according to<6>, wherein in powder x-ray diffraction, the crystal at 15.8 °, 18.4 ° and There is diffraction maximum at 24.4 ° of the angle of diffraction (2 θ ± 0.2 °).

<7.1>crystal according to<6>, wherein in powder x-ray diffraction, the crystal 13.7 °, 15.8 °, There is diffraction maximum at 18.4 ° and 24.4 ° of the angle of diffraction (2 θ ± 0.2 °).

<7.2>crystal according to<6>, wherein in powder x-ray diffraction, the crystal 11.8 °, 13.7 °, There is diffraction at 15.8 °, 17.5 °, 18.4 °, 19.3 °, 21.1 °, 23.6 °, 24.4 ° and 26.0 ° of the angle of diffraction (2 θ ± 0.2 °) Peak.

<8>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl)-of 3- 7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 3 type crystal, In¹³C solid-state In NMR spectra, chemical shift (δ ± 0.5ppm) of the crystal in 64.3ppm, 110.4ppm, 122.7ppm and 127.1ppm Place has peak value.

<9>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl)-of 3- 7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile anhydride 3 type crystal, the crystal With x-ray diffractogram of powder shown in Fig. 3.

<10>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile hydrate crystal (i.e. " hydration Object crystal "), in powder x-ray diffraction, the crystal has diffraction maximum at 5.5 ° of the angle of diffraction (2 θ ± 0.2 °).

<11>crystal according to<10>, wherein in powder x-ray diffraction, the crystal at 5.5 °, 14.0 ° and There is diffraction maximum at 27.2 ° of the angle of diffraction (2 θ ± 0.2 °).

<11.1>crystal according to<10>, wherein in powder x-ray diffraction, the crystal 5.5 °, 8.5 °, There is diffraction maximum at 14.0 °, 15.4 °, 16.1 °, 17.0 °, 22.6 °, 26.5 ° and 27.2 ° of the angle of diffraction (2 θ ± 0.2 °).

<12>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile hydrate crystal, In¹³C solid-state In NMR spectra, the crystal in 63.7ppm, 100.4ppm, 109.6ppm, 117.2ppm, 129.1ppm, 147.3ppm and There is peak value at the chemical shift (δ ± 0.5ppm) of 156.3ppm.

<13>crystal according to<1>, wherein the crystal is the fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridine -3- of 3- Base) -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile hydrate crystal, the crystal With x-ray diffractogram of powder shown in fig. 5.

<14>a kind of pharmaceutical composition, described pharmaceutical composition include the crystal according to any one of<1>to<13> As active constituent.

<15>pharmaceutical composition according to<14>, wherein described pharmaceutical composition is ampa receptor inhibitor.

<16>pharmaceutical composition according to<14>, for treating epilepsy.

<17>a kind of for treating the medicament of epilepsy, the medicament includes the crystalline substance according to any one of<1>to<13> Body.

<18>a kind of method for treating epilepsy, the method includes applying to patient according to any one of<1>to<13>institute The crystal stated.

Advantageous effect of the invention

According to the present invention it is possible to provide the crystal of compound (I), with good physical property and expection can be used as The bulk pharmaceutical chemicals of drug.

Detailed description of the invention

[Fig. 1] Fig. 1 shows the x-ray diffractogram of powder of 1 type anhydride crystal of the compound (I) obtained in example 1. Abscissa shows the angle of diffraction (2 θ), and ordinate shows peak strength.

[Fig. 2] Fig. 2 shows 1 type anhydride crystal of the compound (I) obtained in example 1¹³C solid state NMR spectroscopy.It is horizontal Coordinate shows chemical shift (δ), and ordinate shows peak strength.

[Fig. 3] Fig. 3 shows the x-ray diffractogram of powder of 3 type anhydride crystal of the compound (I) obtained in example 2. Abscissa shows the angle of diffraction (2 θ), and ordinate shows peak strength.

[Fig. 4] Fig. 4 shows 3 type anhydride crystal of the compound (I) obtained in example 2¹³C solid state NMR spectroscopy.It is horizontal Coordinate shows chemical shift (δ), and ordinate shows peak strength.

[Fig. 5] Fig. 5 shows the x-ray diffractogram of powder of the hydrate crystal of the compound (I) obtained in example 3.It is horizontal Coordinate shows the angle of diffraction (2 θ), and ordinate shows peak strength.

[Fig. 6] Fig. 6 shows one kind of the hydrate of the compound (I) obtained in example 3¹³C solid state NMR spectroscopy.Horizontal seat Chemical shift (δ) has been indicated, and ordinate shows peak strength.

[Fig. 7] Fig. 7 is the heat analysis TG-DTA figure of the hydrate crystal of compound obtained in example 3 (I).Horizontal seat Temperature is indicated, left side ordinate has indicated the weight change in TG, and right side ordinate shows the hot-fluid of DTA.

Specific embodiment

It hereinafter will be described in the crystal and preparation method thereof of the compound of the present invention (I).

As used herein, " crystal " refers to the anhydride of compound (I) or the crystal of hydrate.

Preferred compound (I) crystal includes: herein

In powder x-ray diffraction, there is the compound (I) of diffraction maximum at 10.8 ° of the angles of diffraction (2 θ ± 0.2 °) The crystal (1 type anhydride crystal) of anhydride；

In powder x-ray diffraction, there is diffraction maximum at 10.2 °, 10.8 ° and 30.4 ° of the angles of diffraction (2 θ ± 0.2 °) Compound (I) anhydride crystal (1 type anhydride crystal)；

In powder x-ray diffraction, in 10.2 °, 10.8 °, 16.8 °, 26.2 ° and 30.4 ° of the angles of diffraction (2 θ ± 0.2 °) The crystal (1 type anhydride crystal) of the anhydride of compound (I) with diffraction maximum；

In¹³In C solid state NMR spectroscopy, in 65.8ppm, 107.2ppm, 113.4ppm, 126.4ppm, 145.1ppm and (1 type anhydride is brilliant for the crystal of the anhydride of compound (I) at the chemical shift (δ ± 0.5ppm) of 160.1ppm with peak value Body)；

In powder x-ray diffraction, there is the compound (I) of diffraction maximum at 24.4 ° of the angles of diffraction (2 θ ± 0.2 °) The crystal (3 type anhydride crystal) of anhydride；

In powder x-ray diffraction, there is diffraction maximum at 15.8 °, 18.4 ° and 24.4 ° of the angles of diffraction (2 θ ± 0.2 °) Compound (I) anhydride crystal (3 type anhydride crystal)；

In powder x-ray diffraction, have at 13.7 °, 15.8 °, 18.4 ° and 24.4 ° of the angles of diffraction (2 θ ± 0.2 °) The crystal (3 type anhydride crystal) of the anhydride of the compound (I) of diffraction maximum；

In¹³In C solid state NMR spectroscopy, 64.3ppm, 110.4ppm, 122.7ppm and 127.1ppm chemical shift (δ ± 0.5ppm) place has the crystal (3 type anhydride crystal) of the anhydride of the compound (I) of peak value；

In powder x-ray diffraction, the water of the compound (I) at 5.5 ° of the angles of diffraction (2 θ ± 0.2 °) with diffraction maximum Close the crystal (hydrate crystal) of object；

In powder x-ray diffraction, with diffraction maximum at 5.5 °, 14.0 °, 27.2 ° of the angle of diffraction (2 θ ± 0.2 °) The crystal (hydrate crystal) of the hydrate of compound (I)；And

In¹³In C solid state NMR spectroscopy, 63.7ppm, 100.4ppm, 109.6ppm, 117.2ppm, 129.1ppm, Crystal (the water of the hydrate of compound (I) at the chemical shift (δ ± 0.5ppm) of 147.3ppm and 156.3ppm with peak value Solvate crystal).

The diffraction maximum of above-described each powder x-ray diffraction and¹³Chemical shift in C solid state NMR spectroscopy, for changing It is all special for closing 1 type anhydride crystal, 3 type anhydride crystal of compound (I) and the hydrate crystal of compound (I) of object (I) Fixed, therefore, they are the characteristic peaks of each crystal.

In general, there may be the errors in the range of ± 0.2 ° for the angle of diffraction (2 θ) in powder x-ray diffraction.Therefore, it needs It is to be understood that each value of the above-described angle of diffraction further includes the number within the scope of about ± 0.2 ° other than above-mentioned value Value.Therefore, certain compounds are not only included in powder x-ray diffraction with the phase allomeric of the present invention complete with above-mentioned value With the crystal of peak value at the exactly the same angle of diffraction, it is also included in powder x-ray diffraction, within the scope of about ± 0.2 ° of error Also there is the crystal of peak value at the angle of diffraction identical with above-mentioned value.

For example, " the having diffraction maximum at 10.8 ° of the angles of diffraction (2 θ ± 0.2 °) " of this paper in this article refers to " In There is diffraction maximum at 10.6 ° to 11.0 ° of the angle of diffraction (2 θ) ", and it is equally applicable to other angles of diffraction.

In general, the peak strength of the angle of diffraction (2 θ) or half width are different in the powder x-ray diffraction measured every time, this The variation of the size or shape of each particle of the difference or powder crystal as measurement sample depending on measuring condition, i.e., Keep crystal form identical.Therefore, it is always inconstant that peak strength or half width obtained are measured every time.Therefore, in powder X-ray In the comparison of x ray diffration pattern x, even if the peak strength or half width at the identical angle of diffraction (2 θ) have differences, the difference is simultaneously Do not mean that the crystal form of crystal is different.Therefore, when a kind of x-ray diffractogram of powder of crystal and particular crystal of the present invention When characteristic diffraction peak has the difference, it means that the crystal and crystal of the invention crystalline form having the same.In addition, this paper " X-ray powder diffraction figure with Fig. 1 " refers to have and the identical X-ray of x-ray diffractogram of powder shown in FIG. 1 The crystal of powder diagram, and the powder different with characteristic diffraction angles but peak strength same as shown in Figure 1 or half width The crystal of last X-ray diffractogram, it is all same with crystal phase of the invention.

As used herein, phrase " 65.8ppm, 107.2ppm, 113.4ppm, 126.4ppm, 145.1ppm and 160.1ppm Chemical shift (δ ± 0.5ppm) " refer to, "¹³C solid state NMR spectroscopy method under normal measuring condition or with described in specification The essentially identical progress of condition, and in either case, crystal in 65.8ppm, 107.2ppm, 113.4ppm, There is of substantially equal peak value " at the chemical shift (δ ± 0.5ppm) of 126.4ppm, 145.1ppm and 160.1ppm.

In general, when whether determining crystal " has essentially identical peak ",¹³Chemical shift in C solid state NMR spectroscopy may In the presence of the error within the scope of ± 0.5ppm.It is to be understood, therefore, that other than above-mentioned value, above-described chemical shift Each value further include the numerical value within the scope of about ± 0.5ppm.Therefore, with the phase allomeric of the present invention, not only it is included in¹³C solid-state The identical crystal of chemical shift in NMR spectra also includes chemical shift error identical crystalline substance within the scope of about ± 0.5ppm Body.Thus, for example, " the having peak value at the chemical shift (δ ± 0.5ppm) of 65.8ppm " of this paper refers to, " in 65.3ppm There is peak value to the chemical shift (δ) of 66.3ppm ", and be equally applicable to¹³Other chemical potentials in C solid state NMR spectroscopy It moves.

Hereinafter an embodiment of the present invention will be described, the preparation method of the crystal of compound (I).

The method for being used to prepare compound (I)

Compound (I) can be prepared by method well known to those skilled in the art.For example, compound (I) can pass through The synthesis of method described in following reference examples.

The method for being used to prepare the crystal of compound (I)

Description is hereinafter used to prepare to the method for the crystal of compound (I).The crystal of compound (I) can be by as follows Prepared by mode, heat and dissolved compound (I) in a solvent, then under stiring the compound (I) of hot-cold lysis so that chemical combination Object (I) crystallization.For example, the crystal of the hydrate of 1 type of the anhydride of compound (I) and 3 type crystal and compound (I) can lead to It crosses and suitably changes method described in example to prepare.

Compound (I) for crystallization may be any type of.For example, compound (I) can be solvate, hydration Object or anhydride and amorphous substance or crystal (including crystal made of a variety of polymorphs) form, are also possible to its mixing Object.

The example of solvents used for crystallization includes alcoholic solvent, such as methanol, ethyl alcohol, 2- propyl alcohol, 1- propyl alcohol and n-butyl alcohol；Second Nitrile；Amide solvent, such as n,N-Dimethylformamide；Ester solvent, such as ethyl acetate；Saturated hydrocarbon solvent, such as hexane or heptan Alkane；Ketone solvent, such as acetone and 2- butanone；And ether solvents, such as t-butyl methyl ether；And water.These solvents can be independent It uses, it can also two kinds or combination of the above use.It is crystallized with the solvent mixture of aqueous solvent such as second alcohol and water, obtains chemical combination The hydrate crystal of object (I).

The usage amount of solvent can be selected suitably, and as lower limit, amount can make compound (I) by dissolving by heating or making to hang Supernatant liquid can stir, and as the upper limit, amount will not significant reduction crystal yield.

In crystallization, required compound (I) crystal can be added as crystal seed.Solution temperature when adding crystal seed does not have It is particularly limited to, preferably 0 to 80 DEG C.

Temperature when heating and dissolved compound (I) can be according to solvent case, the temperature of appropriate Selective dissolution compound (I) Degree is to determine.Preferably, temperature is in the range of causing reflux temperature for 50 DEG C to solvent, and more preferable 55 to 80 DEG C.

Cooling stage during crystallization is quickly cooled down the available crystal (polymorph) containing various crystal forms.Cause This, preferably while cooling according to the influence (such as quality or crystallite dimension) to crystal, suitably adjusting cooling rate.It is preferred cold But the example of rate includes 5 to 40 DEG C/h.

Final crystallization temperature can suitably be selected according to the yield of crystal or quality etc., but preferably -25 to 30 DEG C.

The crystal obtained after crystallization can be separated by conventional filtration, obtain target crystal.The crystal of filtering is optionally It is washed, and can be further dried with solvent.Solvent for washing crystal can be identical as solvents used for crystallization.Solvent it is preferred Example includes ethyl alcohol, acetone, 2- butanone, ethyl acetate, ether, t-butyl methyl ether and hexane.These solvents can individually make With, can also two kinds or combination of the above use.

The crystal being separated by filtration can be suitably by under atmosphere or under nitrogen flowing or passing through heat drying.

Drying time can determine that this depends on production by proper choice of residual solvent amount lower than the time of predetermined amount Amount, drying equipment, drying temperature etc..Further, it is also possible to be dried under ventilation or under reduced pressure.Degree of pressure reduction can basis Output, drying device, drying temperature etc. suitably select.After drying, it can according to need and stay gained crystal in an atmosphere.

The crystal of the compound (I) obtained by above-mentioned preparation method, such as the activity data in following pharmacology test cases It is shown, there is ampa receptor inhibiting effect, therefore can be used as treating the medicament of epilepsy.

[drug composition]

Another embodiment of the invention is pharmaceutical composition, comprising the crystal of compound (I) and pharmaceutically acceptable Additive.Pharmaceutical composition of the invention can by mix the crystal of pharmaceutically acceptable additive and compound (I) come Preparation.Pharmaceutical composition of the invention can be prepared in accordance with known methods, such as the preparation general rule of the 16th edition Japanese Pharmacopoeia In (General Rules for Preparations of the Japanese Pharmacopoeia 16th Edition) The method of description.

The pharmaceutical composition of the present embodiment can suitably give patient according to dosage form.

The dosage of the compound of the present invention (I) will be according to the severity of illness, age, gender, weight, dosage form or salt Concrete type of type, disease etc. and change；However in general, adult is in the case where oral administration, daily dosage is about 30 μ g to 10g, preferably 100 μ g to 5g, more preferable 100 μ g to 1g, in the case where drug administration by injection, daily dosage be about 30 μ g extremely 1g, preferably 100 μ g to 500mg, more preferable 100 μ g to 300mg, respectively with single or for several times, divided dose is administered.

Example

The crystal of the compounds of this invention (I) can be prepared by, for example, the method described in following instance, and the compound Effect can be confirmed by method described in following test case.It is to be appreciated, however, that these examples are exemplary only, this hair It is bright not limited in any case by example in detail below, and can be changed without departing from the scope of the invention Become.

In the following example, prepared crystal is placed on the sample stage of powder x-ray diffraction and powder X-ray is carried out to it Ray crystallographic, and analyzing crystal under the following conditions.

(measuring condition)

Specimen holder；Aluminum frame

Target: copper

Detector: scintillation counter

Tube voltage: 50kV

Tube current: 300mA

Slit: divergent slit 0.5mm, scatter slit opening, light-receiving slit opening

Sweep speed: 5 °/minute

Sampling interval: 0.02 °

Scanning range: 5 to 35 °

The crystal is measured under the following conditions¹³C solid state NMR spectroscopy.

(measuring condition)

The equipment used: Avance 400MHz (Brooker Co., Ltd (BRUKER Co., Ltd) manufacture) 7mm-CPMAS Probe (Brooker Co., Ltd (BRUKER Co., Ltd) manufacture)

Measurement core:¹³C(100.6248425MHz)

Measure temperature: room temperature (22 DEG C)

Pulse mode: CPTOSS measures (spinning side band removing method)

Speed: 5000Hz

Pulse-recurrence time: 60 seconds

Time of contact: 1 millisecond

Cumulative amount: 2400 times

Reference material: glycine (external reference: 176.03ppm)

Pay attention to the compound etc. that file meaning is prepared according to file etc..

Abbreviation used herein is well known to those skilled in the art Conventional abbreviations.Following abbreviation will be used herein:

(Ataphos)₂PdCl₂: bis- (di-t-butyl (4- dimethylaminophenyl) phosphine) dichloro palladiums (II)

DCM: methylene chloride

DMF:N, dinethylformamide

DMSO: dimethyl sulfoxide

N-: just

NBS:N- bromo-succinimide

THF: tetrahydrofuran

¹H NMR: proton NMR spectrometry

MS: mass spectrography

In following instance and reference example, " room temperature " typically refers to about 10 DEG C to about 35 DEG C.Unless otherwise indicated, " % " Refer to weight percent.

To record relative to the δ unit (ppm) of tetramethylsilane, coupling is normal for chemical shift in proton NMR spectral Number is with hertz (Hz) record.The abbreviation for splitting form-separating is as follows:

S: unimodal, d: doublet, t: triplet, q: quartet, m: multiple to meet, br.s: width unimodal.

The reaction that microwave reactor is used in reference example, uses the initiator from Biotage company^TMOr initiator+^TM。

For chromatography, the Silica Gel60 (70-230 mesh ASTM) produced using Merck (Merck) company or Fuji { column: mountain is kind by the PSQ60B or prepacked column of chemistry of silicones Co., Ltd (Fuji Silysia Chemical Ltd.) production (Yamazen) Hi-Flash of company's production^TMColumn (Silicagel), size: S (16x 60mm), M (20x 75mm), L (26x 100mm), any one of 2L (26 x 150mm) and 3L (46 x 130mm)；Or the Biotage of Biotage company production^TM Size: SNAP super silica gel box uses any one of 10g, 25g and 50g }.

NH silica gel uses Fuji's chemistry of silicones Co., Ltd (Fuji Silysia Chemical Ltd.) production CHROMATOREX NH-DM2035 or prepacked column { column: are apt to the Hi-Flash of (Yamazen) company production in mountain^TMColumn (Amino), size: S (16x 60mm), M (20x 75mm), L (26x 100mm), 2L (26x 150mm) and 3L (46x Any one 130mm)；Or it uses and Wako Pure Chemical Industries Co., Ltd (Wako Pure Chemical Industries, Ltd.) Presep^TM(Luer Lock)NH₂(HC), it size: uses M type (14g/25mL), L-type (34g/70mL), 2L type (50g/ 100mL) and any one of 3L type (110g/200mL).

As neutral alumina, 90 active neutral of aluminium oxide, 70-230 mesh, Merck (Merck), E6NXX are used.

The title of compound as shown below has used " E-Notebook " the 12nd edition (PerkinElmer Co., Ltd (PerkinElmer Co., Ltd.)) on the title that shows, in addition to common reagent.

Reference example 1

The fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl) of 3- -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] connection Pyridine -9- base) benzonitrile synthesis

[chemical formula 5]

(1) synthesis of the bromo- 6- methoxyl group -2- of 3- ((methoxymethoxy) methyl) pyridine

At room temperature, by (the bromo- 6- methoxypyridine -2- base of 3-) methanol (CAS 623942-84-7) (2.15g, 9.86mmol, 1 equivalent), Chloromethyl methyl ether (2.25mL, 29.6mmol, 3 equivalent) and n,N-diisopropylethylamine (8.61mL, 49.3mmol, 5 equivalents) mixture in the DCM solution (45mL) stirring 15 hours.The reaction mixture is dense under reduced pressure Contracting.With silica gel column chromatography (NH silica gel, 0%-5% ethyl acetate/normal heptane) purify residue, obtain title compound (yield: 2.22g)。

MS[M+H]⁺=262

(2) synthesis of (6- methoxyl group -2- ((methoxymethoxy) methyl) pyridin-3-yl) boric acid

By the THF of the bromo- 6- methoxyl group -2- of 3- ((methoxymethoxy) methyl) pyridine (1.09g, 4.16mmol, 1 equivalent) (20mL) solution is cooled to -78 DEG C, and addition n-BuLi (the 2.69M solution in n-hexane, 1.70mL, 4.58mmol, 1.1 Equivalent).The reaction mixture is stirred 1 hour at the same temperature, then add trimethylborate (0.696mL, 6.24mmol, 1.5 equivalents).Reaction mixture is stirred 12 hours, while being warming up to room temperature, is then concentrated under reduced pressure.To residue Middle addition saturated aqueous ammonium chloride, and mixture is extracted with DCM.Under reduced pressure, concentration of organic layers, with silica gel column chromatography (silicon Glue, 10%-100% ethyl acetate/normal heptane) purifying residue, obtain target compound (yield: 570mg).

¹H-NMR (400MHz, CDCl₃) δ (ppm): 3.42 (s, 3H), 3.95 (s, 3H), 4.75 (s, 2H), 4.79 (s, 2H), 6.32 (s, 2H), 6.71 (d, J=8.2Hz, 1H), 8.08 (d, J=8.4Hz, 1H).

MS[M+H]⁺=228

The fluoro- 6 '-methoxyl group -2 '-of (3) 3,5- bis- ((methoxymethoxy) methyl) -2, the synthesis of 3 '-bipyridyls

(6- methoxyl group -2- ((methoxymethoxy) methyl) pyridin-3-yl) boric acid (570mg, 2.51mmol, 1 equivalent), Bromo- 3, the 5- difluoro pyridine of 2- (CAS 660425-16-1) (560mg, 2.89mmol, 1.15 equivalent), potassium fluoride (438mg, 7.53mmol, 3 equivalents), (Ataphos)₂PdCl₂(89mg, 0.126mmol, 0.05 equivalent), Isosorbide-5-Nitrae-dioxanes (12mL) and water The mixture of (3mL) reacts 4 hours at 130 DEG C in microwave reactor.Reaction mixture is cooled to room temperature, then directly It connects and is purified with silica gel column chromatography (silica gel on NH silica gel, 5%-35% ethyl acetate/normal heptane), obtain title compound (yield: 648mg).

MS [M+H] +=297

The synthesis of (4) 3,5- bis- fluoro- 2 '-(methylol)-[2,3 '-bipyridyl] -6 ' -ol

At 55 DEG C, by the fluoro- 6 '-methoxyl group -2 '-of 3,5- bis- ((methoxymethoxy) methyl) -2,3 '-bipyridyls The mixture of (648mg, 2.19mmol, 1 equivalent) and 48% hydrobromic acid aqueous solution (1.98mL, 17.5mmol, 8 equivalent) is in THF It is stirred 8 hours in (15mL) solution.The reaction mixture is cooled to room temperature, is then concentrated under reduced pressure.Add into residue Add saturated sodium bicarbonate aqueous solution and DCM.Mixture is stirred at room temperature 1 hour, gained precipitating is then collected by filtration Object.Obtained solid is washed with water, title compound (yield: 349mg) is obtained.

¹H-NMR (400MHz, DMSO-d₆) δ (ppm): 4.33 (s, 2H), 6.35 (d, J=9.3Hz, 1H), 7.51 (dd, J =9.3,1.8Hz, 1H), 8.04 (ddd, J=10.1,8.9,2.5Hz, 1H), 8.57 (d, J=2.4Hz, 1H).

MS[M+H]⁺=239

(5) synthesis of the fluoro- 6H- pyrans of 3- simultaneously [3,2-b:5,4-b '] bipyridyl -8 (7H) -one

At 100 DEG C, by 3,5- bis- fluoro- 2 '-(methylol)-[2,3 '-bipyridyl] -6 ' -ol (329mg, 1.38mmol, 1 Equivalent) and the mixture of potassium carbonate (573mg, 4.14mmol, 3 equivalent) stirred 5 hours in DMF (7mL) solution.Reaction is mixed It closes object to be cooled to room temperature, then adds aqueous ammonium chloride solution.Mixture is stirred at room temperature 30 minutes, is then received by filtering Collect gained sediment.Obtained solid is washed with water and normal heptane, obtains title compound (yield: 251mg).

¹H-NMR (400MHz, DMSO-d₆) δ (ppm): 5.20 (s, 2H), 6.46 (d, J=8.8Hz, 1H), 7.38 (dd, J =9.7,2.4Hz, 1H), 8.04 (d, J=9.3Hz, 1H), 8.19 (d, J=2.6Hz, 1H).

MS[M+H]⁺=219

(6) synthesis of the fluoro- 7- of 3- (pyridin-3-yl) -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -8 (7H) -one

At 80 DEG C, by the fluoro- 6H- pyrans of 3- simultaneously [3,2-b:5,4-b '] bipyridyl -8 (7H) -one (250mg, 1.15mmol, 1 equivalent), silver carbonate (474mg, 1.72mmol, 1.5 equivalent), cupric iodide (I) (131mg, 0.687mmol, 0.6 Equivalent) and pyridine (0.927mL, 11.5mmol, 10 equivalent) mixture DMF (7mL) and DMSO (9mL) in the mixed solvent Stirring 20 minutes.It is slowly added pyridine -3- the boric acid 1 in DMF (4mL) and DMSO (1mL) into reaction mixture, 3- the third two Alcohol cyclic ester (CAS 131534-65-1) (373mg, 2.29mmol, 2 equivalent) mixed solution.At 80 DEG C, by reaction mixture Stirring 20 hours, then adds on silicagel pad (NH silica gel and silica gel), is eluted with ethyl acetate.Under reduced pressure by the reaction solution It is concentrated.Water is added into residue, and mixture is extracted with ethyl acetate.It is washed with saturated sodium-chloride water solution organic Layer, is then concentrated under reduced pressure.By residue silica gel column chromatography (the NH silica gel on silica gel, 10%-100% acetic acid second Ester/normal heptane, 10% methanol/ethyl acetate) purifying, obtain title compound (yield: 43.5mg).

¹H-NMR (400MHz, CDCl₃) δ (ppm): 4.64-4.73 (m, 1H), 4.77-4.86 (m, 1H), 6.78 (d, J= 9.5Hz, 1H), 6.94 (dd, J=8.9,2.5Hz, 1H), 7.51-7.58 (m, 1H), 7.65-7.72 (m, 1H), 8.14 (d, J= 2.6Hz, 1H), 8.29 (d, J=9.7Hz, 1H), 8.53 (d, J=2.6Hz, 1H), 8.79 (dd, J=4.8,1.5Hz, 1H).

MS[M+H]⁺=296

(7) conjunction of the fluoro- 7- of the bromo- 3- of 9- (pyridin-3-yl) -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -8 (7H) -one At

At room temperature, by 3- fluoro- 7- (pyridin-3-yl) -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -8 (7H) -one The mixture of (43.5mg, 0.147mmol, 1 equivalent) and NBS (31.5mg, 0.177mmol, 1.2 equivalent) are in acetonitrile solution Stirring 15 hours in (3mL).Reaction mixture is directly used to silica gel column chromatography (the NH silica gel on silica gel, 10%-100% acetic acid Ethyl ester/normal heptane) purifying, obtain title compound (yield: 33mg).

¹H-NMR (400MHz, CDCl₃) δ (ppm): 4.60-4.70 (m, 1H), 4.74-4.83 (m, 1H), 6.95 (dd, J= 8.6,2.0Hz, 1H), 7.56 (dd, J=8.1,4.8Hz, 1H), 7.65-7.72 (m, 1H), 8.14 (d, J=2.4Hz, 1H), 8.53 (d, J=2.4Hz, 1H), 8.71 (s, 1H), 8.81 (dd, J=4.9,1.6Hz, 1H).

MS[M+Na]⁺=396

(8) (the fluoro- 8- oxo -7- (pyridin-3-yl) of 3- -7,8- dihydro -6H- pyrans is simultaneously [3,2-b:5,4-b '] by the fluoro- 6- of 2- Bipyridyl -9- base) benzonitrile synthesis

At 130 DEG C, by the bromo- 3- of 9- fluoro- 7- (pyridin-3-yl) -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -8 (7H) -one (16.5mg, 0.044mmol, 1 equivalent), 2- cyano -3- fluorobenzoic boric acid pinacol ester (CAS 765916-91-4) (14.2mg, 0.057mmol, 1.3 equivalent), (Ataphos)₂PdCl₂(1.56mg, 2.21 μm of ol, 0.05 equivalent), triethylamine The mixture of (0.025mL, 0.176mmol, 4 equivalent), Isosorbide-5-Nitrae-dioxanes (0.5mL) and water (0.15mL) is in microwave reactor In reaction 2.5 hours.Reaction solution is directly used to silica gel column chromatography (the NH silica gel on silica gel, 5%-90% ethyl acetate/positive heptan Alkane) purifying, obtain title compound (yield: 11.0mg).

¹H-NMR (400MHz, CDCl₃) δ (ppm): 4.71-4.80 (m, 1H), 4.86-4.95 (m, 1H), 6.97 (dd, J= 8.8,2.4Hz, 1H), 7.20-7.28 (m, 1H), 7.46 (d, J=7.7Hz, 1H), 7.57 (dd, J=8.2,4.8Hz, 1H), 7.63 (td, J=8.2,5.8Hz, 1H), 7.77 (ddd, J=8.1,2.6,1.6Hz, 1H), 8.14 (d, J=2.6Hz, 1H), 8.51 (s, 1H), 8.60 (d, J=2.6Hz, 1H), 8.81 (dd, J=4.9,1.6Hz, 1H).

MS[M+H]⁺=415

<example 1>

The fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl) of 3- -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] connection Pyridine -9- base) benzonitrile 1 type anhydride crystal preparation

The fluoro- 6- of 2- described in the reference example 1 of 3.2g (fluoro- 8- oxo -7- (pyridin-3-yl) -7, the 8- bis- of 3- will be weighed Hydrogen -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile is added in eggplant type flask, and adds 160mL thereto N-butyl alcohol, with blender stir acquired solution, obtain suspension.Resulting suspension is stirred at room temperature 2 days.It filters The solid arrived obtains the 1 type crystal (yield: 2.8g) of the anhydride of title compound.It should be noted that 1 type anhydride of the example Crystal is not to start to obtain by 3 type anhydride crystal of example 2.

The angle of diffraction (2 θ ± 0.2 °) in X-ray powder diffraction: 5.1,8.7,10.2,10.8,11.6,15.4,16.8, 18.7、19.6、21.1、23.4、24.9、26.2、27.1、28.1、30.4、31.0

¹³C-NMR (100MHz, solid-state) δ (ppm): 65.8,103.5,107.2,113.4,114.7,123.9,124.7, 126.4,131.6,133.9,135.6,142.4,145.1,148.7,152.9,157.2,160.1,161.9

Obtained x-ray diffractogram of powder is as shown in Figure 1, obtain¹³C solid state NMR spectrum is as shown in Figure 2.

<example 2>

The fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl) of 3- -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] connection Pyridine -9- base) benzonitrile 3 type anhydride crystal preparation

Weigh the fluoro- 6- of 2- described in the reference example 1 of 2.2g (fluoro- 8- oxo -7- (pyridin-3-yl) -7, the 8- bis- of 3- Hydrogen -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile is added in eggplant type flask, and adds 44mL's thereto N-butyl alcohol stirs acquired solution with blender, obtains suspension.At 40 DEG C, by mixture stirring 2 hours of acquisition, then It is stirred at room temperature 3 days.The solid being obtained by filtration obtains the 3 type crystal (yield: 2.1g) of the anhydride of title compound.

The angle of diffraction (2 θ ± 0.2 °) in X-ray powder diffraction: 11.8,13.7,15.8,17.5,18.4,19.3,21.1, 22.2、23.6、24.4、25.5、26.0、27.0、33.0

¹³C-NMR (100MHz, solid-state) δ (ppm): 64.3,103.1,110.4,111.9,114.7,122.7,127.1, 131.5,135.6,142.0,149.0,150.5,152.5,157.3,159.0,161.5

Obtained x-ray diffractogram of powder is as shown in figure 3, obtain¹³C solid state NMR spectrum is as shown in Figure 4.

<example 3>

The fluoro- 6- of 2- (the fluoro- 8- oxo -7- (pyridin-3-yl) of 3- -7,8- dihydro -6H- pyrans simultaneously [3,2-b:5,4-b '] connection Pyridine -9- base) benzonitrile hydrate crystal preparation

Weigh the fluoro- 6- of 2- described in the reference example 1 of 39mg (fluoro- 8- oxo -7- (pyridin-3-yl) -7, the 8- bis- of 3- Hydrogen -6H- pyrans simultaneously [3,2-b:5,4-b '] bipyridyl -9- base) benzonitrile is added in test tube, and adds 50% (v/v) thereto Ethanol water, with blender stir acquired solution, obtain suspension.Then, obtained suspension is stirred at room temperature 10 days.The solid being obtained by filtration, obtains title compound.

The angle of diffraction (2 θ ± 0.2 °) in X-ray powder diffraction: 5.5,6.4,8.5,14.0,15.4,16.1,17.0, 22.6、25.8、26.5、27.2

¹³C-NMR (100MHz, solid-state) δ (ppm): 63.7,100.4,103.5,109.6,111.8,117.2,125.3, 129.1,134.0,136.2,142.4,143.3,146.1,147.3,149.5,151.0,153.0,156.3,159.3, 160.8,161.7,164.1

Obtained x-ray diffractogram of powder is as shown in figure 5, obtain¹³C solid state NMR spectrum is as shown in Figure 6.

<measurement of heat analysis TG-DTA>

By crystal obtained in example 3 (hydrate crystal) accurate weighing in aluminium sample disc, and survey under the following conditions Amount.By heating, hydrate crystal release water outlet is converted to the anhydride crystal different from 1 type crystal and 3 type crystal.When When being restored to room temperature, anhydride absorption of crystal water simultaneously again returns to original hydrate crystal state.

(measuring condition)

Atmosphere: the nitrogen flow lower than 40mL/ points

Control: empty aluminium sample disc

Heating speed: 10 DEG C/minute

Sampling interval: 0.1 second

Measure temperature: room temperature is to 230 DEG C

As the result is shown in Fig. 7.

<pharmacology test case>

About the ampa receptor inhibiting effect of compound (I), the originally culture of fetal rat Cortical Neurons is used Calcium enters inhibiting effect in the neuron of system detection AMPA induction.

Calcium enters inhibiting effect in the nerve of AMPA induction

(condition of culture)

Gestational age the 18th day (Japanese Charles River Laboratories (CHARLES RIVER LABORATORIES JAPAN, It is anaesthetized when INC.)) with isoflurane, entire tire mouse is taken out from the uterus of Wistar rat.Whole brain is taken out from entire tire mouse, and Cerebral cortex is separated in the L-15 culture medium of Leibovitz or the Hanks balanced salt solution containing 20% fetal calf serum.By institute Substance is obtained to be handled 45 to 60 minutes at 37 DEG C with trypsase/DNA enzymatic solution.Serum is added to stop trypsase reaction Afterwards, obtained material is centrifuged 3 to 5 minutes with the speed of 1200-1500rpm.After removing supernatant, neuron basis is added (Neurobasal) culture medium (contains 2% B-27 replenishers etc.；Hereinafter referred to as " neuron basis culture medium "), by gently Liquid relief keeps cell evenly dispersed.Cell suspending liquid is slightly stirred, is then filtered by nylon mesh filter.Use haemocyte Counter living cell counting, and 8 to 10 × 10 are diluted to neuron basis culture medium⁵A cell/mL.Cell is with every 100 μ of hole L is inoculated into 96 orifice plates, and in CO₂Incubator (5%CO₂, 37 DEG C) in culture.Culture medium, culture 7 are replaced in culture after 24 hours It is tested to 21 days neurons for following pharmacology.

On the day of pharmacology test, with Fura 2-AM (140mmol/L sodium chloride, 5mmol/L chlorine containing 5-10 μm of ol/L Change potassium, 2mmol/L magnesium chloride, 3mmol/L calcium chloride, D (+)-glucose of 24mmol/L, 10mmol/L HEPES, 1 μm of ol/ The MK-801 of L, pH 7.4)) calcium measurement solution replace culture medium, cell is in CO₂Incubator (5%CO₂, 37 DEG C) in culture 1 to 2 hours.It then removes the calcium containing Fura2-AM solution and measures solution, wash the neuron two in each hole with calcium measurement solution It is secondary, 50 μ L calcium measurement solution is then added into each hole.Then, 50 μ L, 3 times of test compound higher than ultimate density is added Or culture medium, and by cell pretreatment about 15 minutes.Orifice plate is then placed in (the You Binsong photon of fluorescent drug screening system 6000 Learn Co., Ltd. (Hamamatsu Photonics K.K.) manufacture).Solution system is measured by adding 50 μ L calcium to each hole The AMPA of 3.3 μm of standby ol/L stimulates solution to stimulate cell.When the fluorescence intensity change of 340nm and 380nm excitation wavelength (measurement wavelength: 540nm), measures the variation of calcium concentration.The change rate of intracellular calcium concentration is calculated according to the following formula:

Intracellular calcium concentration increment rate (% control)=(T_Afterwards-T_Before)/(C_Afterwards-C_Before)x 100

Wherein T_Afterwards: the fluorescence intensity of sample well after stimulation；T_Before: the fluorescence intensity of sample well before stimulating；C_Afterwards: it is compareed after stimulation The fluorescence intensity in hole；C_Before: the fluorescence intensity of control wells before stimulating.

IC for the AMPA test compound inhibited₅₀Value by under various concentration intracellular calcium concentration advance the speed really It is fixed.

As the result is shown in table 1.These are the result shows that compound (I) has enough ampa receptor inhibiting effect.

[table 1]