TW201034673A - Novel salt of 1,3,5-triazine-2,4,6-triamine derivative - Google Patents

Abstract

Anytime obtained is uniform crystal of N-(4-fluorophenyl)-N'-phenyl-N''-(pyrimidin-2-ylmethyl)-1, 3, 5-triazine-2, 4, 6-triamine(compound A) and/or N, N'-bis(4-fluorophenyl)-N''-(pyrimidin-2-ylmethyl)-1, 3, 5-triazine-2, 4, 6-triamine(compound B) as a medicament or a starting material for the preparation of the medicament, and provided are a fumarate of the compound A and/or the compound B having excellent stability and a novel crystal thereof. A salt of the compound A and/or the compound B with fumaric acid enables uniform crystal to be anytime obtained, and thus, it is a compound that is very useful as a medicament or a starting material for the preparation of the medicament having excellent stability.

Description

201034673 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a drug, particularly to N-(4-fluorophenyl)-N'-phenyl-N which can be used as a specific potassium channel inhibitor. -(pyrimidin-2-ylindenyl)-1,3,5-trinol-2,4,6-triamine (hereinafter referred to as compound A) and/or hydrazine, Ν'-贰 (4-fluorobenzene) A novel salt of -)"-""(pyrimidin-2-ylindenyl)-1,3,5-tris-2,4,6-triamine (hereinafter referred to as the compound hydrazine). [Prior Art] It is known that the compound hydrazine and/or the compound hydrazine has the following chemical structural formula, has the effect of inhibiting the specific potassium channel (BEC1 potassium channel) and antidepressant action, and can be used for the treatment of dementia (US Patent Case No. 7,375,222, incorporated herein by reference). [Chemical Formula 1]

Compound A Compound B In particular, the compound A is a composition of the compound A · 2 HC1 · 0.3 H20 · 0.1 ethyl acetate (US Patent No. 7,375,222, hereby incorporated by reference), but Specific reports of other pharmaceutically acceptable acid addition salts. In addition, Compound B is only a virtual example (U.S. Patent No. 099109852 4 201034673 7,375, 222, incorporated herein by reference). SUMMARY OF THE INVENTION Compound A has a pKa value of 3.9 and a low alkalinity. In this respect, it is usually preferred to form a salt with a strong acid. The dihydrochloride salt of Compound A is known as a compound having a typical strong acid, that is, hydrochloric acid as a counter ion, which is obtained as an anhydrous crystal and does not contain a residual solvent, but is observed by differential scanning calorimetry (DSC) analysis. An endothermic peak, so there may be several crystal forms coexisting. It is well known that even if C) is a compound having the same structural formula, the solubility or stability of the compound differs when it has a different crystal form. In order to ensure the consistency of the quality or stability of the drug, it is preferred to select a compound which allows the same crystalline form to be obtained at any time or a preparation method thereof. As for the α-α 3 ', no specific compound has been obtained. But in fact, in order to ensure the drug U or stability, it is better to allow the same knot at any time.

The crystalline form of the compound (free test or limb acid addition) and its preparation method; and in the case where a solvate is obtainable, a pharmaceutically acceptable solvate is preferred, and the compound is also suitable.

The present invention is a compound of AAB or its addition to (4) a base or an acid. The result is _(d), which is known as the -H(tetra) crystal, the specific non-volatile acid addition salt, and the crystal. The invention has excellent stability and properties. The object of the present invention is to provide a compound comprising the formula (I): 099109852 201034673

(wherein R1 is Η or F) and a salt of antibutmental diacid. Another object of the invention is to provide crystals of the compound of formula (I). Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of a compound of formula (I) and an additional pharmaceutically acceptable ingredient. The fumarate of the compound A of the present invention (wherein the compound of the formula I wherein R1 is H) has the advantage that the former compound disulfate of the compound A is compared with the known compound, and the former allows uniform crystals to be obtained at any time, and is excellent as Stabilizing drugs or active ingredients are extremely useful compounds. Further, the compound of the present invention (the compound of the formula I, wherein "the cleavage of the fumarate also allows uniform crystals to be obtained at any time" is a compound which is extremely useful as a pharmaceutical or active pharmaceutical ingredient having excellent stability. In particular, it is disclosed that a homogeneous crystal can be obtained at any time on the shell. It is known that the compound II of the compound A does not allow uniform crystals to be obtained, and has an unavoidable requirement when the developed product is selected. Preparation of a crystal having a certain (four) specification of solubility or stability. The fumarate of Compound A and / or B promotes the provision of an excellent drug because it allows for uniformity at all times, and Excellent (4) Stability. 099109852 201034673 Deuterium 8 and/or Compound B can inhibit the dysmotility of animals that are involved in schizophrenia. The effect of wisdom and the effect of improving the symptoms of schizophrenia. [Embodiment] * The compound of the U, the fumarate and/or the compound B The anti-butene 酉 风 允 ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° 一致性 一致性 一致性 一致性 一致性 一致性 一致性 一致性 一致性 一致性 一致性 一致性 一致性 一致性Good has the ratio of compound a to fumaric acid

It is a salt of 2:1 and/or a salt having a ratio of compound B to fumaric acid or a crystal thereof. I Preferred embodiments of the present invention are shown below. (1) An anhydrous salt having a ratio of compound A to fumaric acid of 2: hydrazine. (2) A crystal having a ratio of the compound A to the fumaric acid of 2: an anhydrous salt of ruthenium. (3) The crystal as described in (2) wherein the endothermic onset temperature in the DSC is about 190 °C. (4) The crystal according to (2), characterized in that in the powder X-ray analysis using copper as an anode, 2 Torr (degrees) is shown at about 5.3, about 8.2, about 10.5, and about 16.4. (5) The crystal according to (2), characterized in that in the powder X-ray analysis using steel as an anode, 2 Θ (degrees) is shown at about 5.3, about 8.2, about 9.8, about 10.5, 099109852 7 201034673 11.7, a peak of about 16.4, about 18, 6, and about 26.6. (6) The crystal as described in (2) is characterized in that the endothermic onset temperature in the DSC is from 180C to 200 C' and in the powder X-ray analysis using copper as the anode, the 2 Θ (degrees) display It is about 5.3, about 8.2, about 10.5, and about 16.4. (7) The crystal according to (2), characterized in that the endothermic onset temperature in the DSC is from 180 ° C to 2 ° C, and in the powder calender analysis using copper as an anode, 2 Θ (degrees) is shown at about 5.3, about 8.2, about 9.8, about 1 〇, 5, about 11 7 , about 16.4, about 18.6, and about 26.6. (8) The crystal as described in (2) to (7), which is an I-type crystal. (9) A pharmaceutical composition comprising as an active ingredient a salt comprising a compound strontium and fumaric acid, and further comprising a pharmaceutically acceptable carrier. (10) The pharmaceutical composition according to (9), wherein the active ingredient is a salt having a ratio of compound A to fumaric acid of 2:1. (11) The pharmaceutical composition according to (9), wherein the active ingredient is an anhydrous salt having a ratio of compound A to fumaric acid of 2:1. (12) A pharmaceutical composition comprising (2) to (the crystal described in the item as an active ingredient, and containing less pharmaceutically acceptable carrier. (13) - Compound A having 2:1 A salt of a ratio of fumaric acid which is a hydrate having a ratio of compound A to water of 2: 1. (14) A crystal of a compound as described in (13) (15) as (14) The crystal according to the item, wherein the endothermic onset temperature in the Dsc is about 150 ° C. The crystal according to the item (14) is characterized in that the powder is used as the anode of the powder X. In the optical analysis, 2 Θ (degrees) is shown at a peak of about 6.7, about 7.8, about 20.1, and * about 20.5. (17) The crystal of the item (14) is characterized by the use of steel as the anode. In powder X-ray analysis, 2 Θ (degrees) is shown at about 6.7, about 7.8, about 8j, about 10.5, about 13.9, about 2 〇.1, about 20.5, and about 21.6. (18) as in item (14) The crystal is characterized in that the endothermic temperature in the DSC is from 140 ° C to 160 ° C, and in the optical analysis using copper as the anode, 2 Θ (degrees) is shown in 6.7, about 7.8, about 20 BU and a peak of about 2〇.5. (19) The crystal according to (14), characterized in that the endothermic onset temperature in the DSC is from 140 ° C to 160 ° C, and in the powder X-ray analysis using copper as the anode, 2 Θ (degrees) ) shows a peak of about 6.7, about 7.8, about 8.1, about 10.5, about η 9, about 20.1, about 20.5, and about 21.6. (20) The crystal according to (14) to (19) which is a quinoid crystal. 〇 (21) A pharmaceutical composition comprising the salt as described in (U) as an active ingredient, and further comprising a pharmaceutically acceptable carrier. (22) A pharmaceutical composition 'comprising the crystals as described in (14) to P) as an active ingredient, and further comprising a pharmaceutically acceptable carrier. (23) A salt having a ratio of the compound A of 1.1 to the anti-butanyl acid. P4) - an anhydrous salt having a ratio of compound A to fumaric acid of 1:1. (25) A crystal of a compound as described in (23) or (24). (26) The crystal as described in (25) wherein the endothermic onset temperature in the DSC is 099109852 9 201034673 degrees is about 160 °C. (27) A crystal according to (25), characterized in that in the powder X-ray analysis using copper as an anode, 2 Θ (degrees) is shown at a peak of about 6.7, about 17.7, about 22.3, and about 26.3. (28) The crystal according to (25), characterized in that in the powder X-ray analysis using copper as an anode, 2 Θ (degrees) is shown at about 6.7, about 9.5, about 11.5, about 13.4, about 16.4, about 17.7, about 22.3, and a peak of about 26.3. (29) The crystal according to (25), characterized in that the endothermic onset temperature in the DSC is from 150 ° C to 170 ° C ' and in the optical analysis using copper as the anode and in the optical analysis ) shows peaks at about 6.7, about 17.7, about 22.3, and about 26.3. (30) The crystal according to (25), characterized in that the endothermic onset temperature in the DSC is from 150 ° C to 170 ° C, and in the powder X-ray analysis using copper as the anode, 2 Θ (degrees) ) shows peaks at about 6.7, about 9.5, about 11.5, about 13.4, about 16.4, about 17.7, about 22.3, and about 26.3. (31) The crystal as described in (25) to (30), which is a type III crystal. (32) A pharmaceutical composition comprising the salt as described in (23) as an active ingredient, and further comprising a pharmaceutically acceptable carrier. (33) A pharmaceutical composition comprising the compound as described in (24) as an active ingredient, and further comprising a pharmaceutically acceptable carrier. (34) A pharmaceutical composition 'comprising crystals as described in (25) to (31) as an active ingredient' and further comprising a t-acceptable carrier. 099109852 10 201034673 (35) —Anhydrous salt ′ is a ratio of compound B to fumaric acid of 1:1. (36) A crystal of a compound as described in (35). (37) The crystal of (36), wherein the endothermic temperature in the DSC is about 215 °C. (38) The steroid according to (36), characterized in that in the powder X-ray analysis using steel as an anode, 2 Θ (degrees) is shown at about 6.6, about 8.2, about 15.7, and about 26.5. . (39) The crystal according to (36), characterized in that in the powder X-ray analysis using copper as an anode, 2 Θ (degrees) is shown at about 8, 2. 2, about 9.2, about 10.9, about 13.6, about I5.7, about 2〇.5, and a peak of about 26.5. (40) The crystal according to (36), characterized in that the endothermic onset temperature in the DSC is from 200 ° C to 22 ° C ' and in the powder X-ray analysis using steel as the anode, 2 Θ ( The degree is shown at about 6.6, about 8.2, about 15.7, and about 26.5. (41) The crystal according to (36), characterized in that the endothermic temperature in the DSC is from 205 t: to 225 ° C, and in the optical analysis using copper as the anode, 2 Θ (degrees) ) shows peaks at about 6.6, about 8, 2, about 9.2, about 109, about 13 6 , about 15.7, about 20.5, and about 26.5. (42) The crystal as described in (36) to (41), which is an I-type crystal. (43) A pharmaceutical composition comprising a salt comprising a compound B and fumaric acid as an active ingredient' and further comprising a pharmaceutically acceptable carrier.夂(44) A pharmaceutical composition comprising as an active ingredient a salt having a ratio of compound B to a di-dicarboxylic acid of 1 ··丨, and further comprising a pharmaceutically acceptable carrier 099109852 201034673 (45) 'Includes a salt as described in (35) as an active ingredient, and further comprises a pharmaceutically acceptable carrier. (46) A drug composition comprising 'the crystals as described in (36) to (4) as an active ingredient, and further comprising a pharmaceutically acceptable carrier. The fumarate salt of the compound of formula (1) can form a solvate. Thus, a salt which is not a solvate but which may have a residual solvent is 'conveniently' described herein as an anhydrous salt. The compound of the formula (1) and the fumaric acid may form a salt in various ratios, and thus, in some cases, crystals of salts in various ratios may be obtained from the towels. When verifying the identity of salt and crystals, the compound of formula (I) should be interpreted in a narrow sense for the anti-succinic acid' because the ratio should not be derived from elemental analysis, powder calender diffraction pattern, DSC, etc. The results of the analysis were determined in an integrated manner. This description also applies to these solvates. In addition, in the powder X-ray diffraction pattern, the verification of the crystal identity is of great importance due to the nature of the data, the diffraction angle or the entire pattern, so the relative intensity depends more or less on the directionality of the crystal growth, the particle size and The measurement conditions 'so should not be interpreted in a narrow sense. Further, the present invention encompasses pure type I crystals of the compound D-succinic acid salt, pure type II crystals, and pure m-type crystals, pure crystals of the compound VIII free-salt base, and fumaric acid of the compound B. A pure crystalline Form 1 crystal of the salt, and a pure crystalline form of the dihydrochloride salt of Compound B, and is considered to be substantially equivalent to a mixture of such pure crystals falling within the scope of the present invention. 099109852 12 201034673 In some cases, the values obtained from a variety of spectra have errors due to crystal growth directionality, particle size, and measurement conditions. Thus, in the present invention, the term "about" used for the diffraction angle (2 Θ) value of the powder X-ray diffraction pattern indicates that the value is almost the same, and preferably indicates that the value may not be greater than or less than the value. The value is equal to 2.2 (degrees). More preferably, the values are not greater than or less than the values up to 1.1 (degrees). In addition, the term "about" for the endothermic initiating temperature value in the DSC indicates that the temperature value of the endothermic start (extrapolation start) temperature is greater than or equal to the value. 2. (:, more preferably, the values are not greater than or less than the values up to 1 ° C. The "anhydrous salt crystal having a ratio of compound a to fumaric acid of 2:1" of the present invention may be subjected to a preparation method Obtained, the method comprises the steps of: arranging crystals of a fumarate of compound A by recrystallization using fumaric acid of 0.9 to 1.1 mole equivalents relative to compound A, and 2) heating The resulting "salt having a ratio of compound A to fumaric acid of 1:1" is suspended in a solvent while adjusting the water content in the solvent to not more than 〇5%. 1) for use in the recrystallization of fumaric acid in an amount of equimolar amount relative to the compound A, and to leave the "anhydrous salt crystal having a ratio of the compound A to the fumaric acid of 2.1" Examples of the recrystallization solvent used in the step preferably include a mixed solvent of ethanol-isobutyl ketone, a mixture of isobutyl ketone, acetone dimethyl dimethyl benzoate (Dms &), a granule, and acetone-DMSO-ethanol. Mixed solvent. In the case of using a mixed solvent of ethanol_isobutyl ketone, the amount of the solvent used for recrystallization may be from 21 parts by weight to 30 parts by weight based on the compound A used in the case of 099109852 13 201034673. The amount of ethanol to isobutanone is preferably from 1: to 4.3. In the case of using isobutyl ketone alone, 16 parts by weight to 35 parts by weight can be used with respect to the compound A to be used. In the case of using a mixed solvent of acetone-DMSO, about 50 parts by weight relative to the compound A can be used. Acetone versus DMSO is preferably about 50:1. In the case of using a mixed solvent of acetone-DMSO-ethanol, 32 parts by weight to 33 parts by weight can be used with respect to the compound A used. For DMSO, about 10 times the amount of acetone and about 11 times the amount of ethanol are preferably used. Recrystallization can be carried out by a known method. 2) As for the suspension of the "salt having a ratio of compound a to fumaric acid of 1:1" to the bath while adjusting the water content to not more than 〇·5% for heating and suspension The solvent is preferably, for example, ethanol. For the amount of solvent used for heating under suspension, 10 parts to 20 parts by weight n t 相对 can be used with respect to the compound A used in the case of using B.

The 5 turns ratio and the heating temperature are preferably from 5 ° C to 75 ° C. The "anhydrous salt crystal having a ratio of a 2:1 compound to a fumaric acid" of the present invention can also be obtained by the following method: wherein the compound a is 0.9 to 1 with respect to the compound A. 1 Moer Dangdun owes the butyric acid to the solvent under heating, while adjusting the water content of the solvent | Xiazhi is not more than 〇.5〇 / 0. As the solvent for suspending under heating, 'e.g., Α horse ethanol is preferable. With respect to the amount of the solvent, in the case of ethanol, about 20 parts by weight relative to the compound used, and the heating temperature is preferably from 6 (TC to 7 Torr. [099109852 14 201034673]

The "salt crystal having a ratio of the compound A to the fumaric acid of 2:1, which is a hydrate having a ratio of the compound A to water of 2:1" of the present invention can be obtained by a seed preparation method, and the method comprises 1) Crystallizing a crystal having a salt of a compound A to a ratio of 1:1 of fumaric acid by recrystallizing fumaric acid with a molar ratio of 〇9 to 丨.1 with respect to the compound A And the 2) the step of "resolving the crystal having the ratio of the compound A to the fumaric acid to the salt of 丨:i" in a solvent while adjusting the water content to not less than 5%. 〇丨) for separating crystals of "a salt having a ratio of compound A to fumaric acid of 1:1" by recrystallization using equimolar amount of fumaric acid relative to compound A. The solvent conditions and the like used in the steps are as described above. 2) As for the step of suspending the "crystal having a salt of the compound A to the fumaric acid ratio of i: i" in a solvent while adjusting the water content to not less than 5% for heating The solvent to be suspended is preferably, for example, ethanol. For the amount of the solvent used for heating under suspension, in the case of ethanol, the ratio of the weight of the salt having a salt of 1:1 with respect to the anti-butanic acid is used. The heating temperature is preferably from 55 〇 c to 65. (: The "hydrate having a ratio of compound A to fumaric acid of 2:1 is a hydrate having a ratio of compound A to water of 2:1" in the present invention. Wherein the compound A is recrystallized with crystals formed by 0.5 to 〇.6 Motino quinone fumarate relative to the compound A, and the water content of the solvent is reduced to not less than 1%. It is carried out by a known method. It is used for the recrystallization of ruthenium 099109852 15 201034673 enedic acid salt which is 0.5 to 0.6 mol equivalent with respect to compound A, and has a ratio of "having compound A to fumaric acid". An example of a recrystallization solvent in a salt of 2:1, which is a hydrate having a compound A to water ratio of 2:1, preferably comprises a mixed solvent of ethanol, DMSO-water, DMSO-acetone-water A mixed solvent' and a mixed solvent of DMSO-acetonitrile-water. Preferably, in the case of ethanol having a water content of 1 〇/〇, a recrystallization solvent is used in an amount of 55 parts by weight based on the compound A used. In the case of a mixed solvent of water, the amount of the recrystallization solvent may be relative to the The compound A used is about 8 parts by weight. The ratio of DMSO to water is preferably about 3: 1. In the case of a mixed solvent of DMSO-acetone-water, 'about 23 parts can be used relative to the compound A used. The ratio of the weight ratio of DMSO to acetone is preferably about 1:2.5: 2.3. In the case of a mixed solvent of DMSO-acetonitrile-water, about 15 parts by weight can be used with respect to the compound A used. The amount of DMSO to acetonitrile to water is preferably about 1:2.5: 0.25. The fumarate of Compound A of the present invention and/or the fumarate of Compound B are used as an active ingredient, in other words. The preparation comprising the fumarate of the compound A of the present invention or the fumarate of the compound b can be used for the preparation of a medicament by combining a pharmaceutically acceptable carrier, an excipient or the like. It is carried out according to the method generally used in the art. The drug comprising the fumarate of the compound A of the present invention or the fumarate of the compound B may be a permeate, a pill, a capsule, a granule, a powder, a solution or the like for oral administration And any preparation form, suppository, transdermal preparation, ointment, transdermal patch, transmucosal liquid preparation which can be administered by intra-articular injection, intravenous injection or intramuscular injection for parenteral injection through the injection of 099109852 16 201034673 , wearing a mucosal patch, an inhalant, etc. In particular, a crystal of an acid addition salt of Compound A as a starting material for the preparation, a tablet, a pill, a capsule, a granule and a powder for oral administration These preparations can be excellently used as a stable solid preparation. Regarding the solid composition of the present invention for oral administration, one or more living Q ingredients are mixed with at least one inactive diluent such as lactose, mannitol, glucose. , hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and / or aluminum magnesium metasilicate. In a conventional method, the composition may contain, in addition to the diluent, an inactive additive such as a lubricant such as stearic acid, a disintegrating agent such as calcium cellulose glycolate, a stabilizer, and a dissolution aid. The tablet or pill may be coated with a sugar coating film or a gastric or enteric coating such as vegetable, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like as the case requires.液体 The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and contains inert diluents generally used, such as purified water and ethanol. In addition to the inert diluent, the composition may contain adjuvants such as wetting and suspending agents, sweetening, flavoring, perfuming, and preservatives. Injections for parenteral administration include sterile aqueous or nonaqueous liquid preparations, suspensions and emulsions. As the aqueous solvent and suspension, for example, steamed crane water for injection and physiological saline are included. Examples of non-aqueous solvents and suspending agents 099109852 17 201034673 include propylene glycol, polyethylene glycol, vegetable oils such as eucalyptus oil, alcohols such as ethanol, and polysorbate 80 (Pharmacopoeia). The composition may contain auxiliary agents such as a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, a dissolution aid, and the like. Such chemical agents are sterilized, for example, by overfishing, by mixing a bactericide or by illuminating the filter by retaining the bacteria. Alternatively, it can be used by making a sterile solid composition and dissolving the composition in sterile water or a sterile injectable solution before use. Since the pharmaceutical composition of the present invention contains the fumarate of the compound A belonging to the BE C1 potassium channel inhibitor and/or the fumarate of the compound b as its active ingredient, it can also be used for the use of potassium BEC1. Treatment or prevention of multiple diseases of channel inhibitors. In other words, the pharmaceutical composition of the present invention is particularly useful as an agent for treating or preventing, for example, dementia. The medicament for use in the present invention is administered orally to a patient suffering from dementia, and the dose per dose is suitably from about 0.001 to 100 mg/kg body weight, administered in one portion or divided into two to four divided doses. In the case of intravenous administration, the daily dose is suitably from about 0.0001 to 1 mg/kg body weight, administered once or twice daily or multiple times per day. Further, the transmucosal preparation is administered at a dose of from about 1 to about 1 mg/kg of body weight, which is administered twice or several times per week or once per week. The dose is appropriately determined in response to individual conditions by considering the individual's symptoms, age, sex, and the like. [Embodiment] The details of the present invention will be described hereinafter with reference to the embodiments, but the present invention is not intended to be limited to the embodiments, and the scope of the present invention is not limited thereto. Further, thermal analysis and powder X-ray diffraction were carried out in the following manner. ' (1) Thermal analysis' Differential scanning calorimetry (DSC) Approximately 3 mg of sample settled in a dedicated sample tray for elevated nitrogen (5 〇 ml/min) and l 〇 ° C/min The rate, measured from room temperature to 300^, continuously measures and records the change in heat generated between the sample and the reference material (blank molded sample tray). In addition, the operation of the device, including data processing, is performed in accordance with methods and procedures that are not indicated by the devices. (Installation: Hi-Res DSC 2910, DSC Q20, Texas Instruments (ΤΑ! her job (4)). Thermogravimetric analysis (TG) Approximately 5 mg of sample settled in a dedicated platinum sample pan under nitrogen Under the environment (5 〇ml/min) and the heating rate of 10C/min, the weight change of the sample is measured and recorded under the following conditions from room temperature to 300. In addition, the operation of the device includes data processing. It is carried out according to the method and procedure indicated by each device. (Device·Hai Rui Si TGA2950, TGAQ50, manufactured by Texas Instruments). (2) Powder X-ray diffraction about 10 oz samples are contained in special sample containers (width 5 mm) 'Length 18 mm, and 0.2 ft deep" 'Continuously measure and record the powder X-ray diffraction _ under the following conditions. In addition, the operation of the device includes data processing instructions for each device 099109852 19 201034673 instructions and procedures (Device: MXP18TAHF22, Mike Science Corporation (訄8 €3 (^11(^) (current name: Bruker (price 11)^))) (Condition) For Figure 3 and Figure 13, Anode: Copper , wavelength: 154 〇 56 angstroms, Measurement range _ 2.50 degrees to 40.00 degrees 'Sampling interval: 〇〇 2 degrees, scanning rate: 4 / / min, tube voltage · · 40 kV, tube current · · 2 mA, div. Variable (radiation width 5.00 mm), scattering slit: variable (radiation width 5. mm), receiving slit: 0.15 mm. For Figures 1, 2, 4, 5 and 6, anode: copper, wavelength :^是泊矣, range: 3.02 degrees to 40.00 degrees, sampling interval: 〇〇 2 degrees, scanning rate: 3.00 degrees / minute 'tube voltage: 40 kV, tube current: 200 mA, politic slit .1.00 degree 'scattering slit: 1.00 degree, receiving slit: mm. In addition, the diffraction angle and diffraction intensity are more or less depending on crystal growth, particle size, measurement conditions, etc. In addition, the following abbreviations are used in the following Reference Examples, Examples and Tables. mp: melting point, FAB+: FAB-MS (M+H)+, El: EI-MS (]V〇+, ESI+: ESI-MS (M+H)+, NMR-DMSOd6: δ (ppm) at the peak of DMSO-d6, DMF: Ν, Ν-dimercaptoamine, DMS 〇: > 肀石石, THF: Hydrogenfuran ' 4M hydrogen chloride / diterpene α mountain solution: 4 Mojie / chlorinated dihydrochloride. Mountain solution, MeCN: acetonitrile, MeOH: decyl alcohol, Et〇ii: ethanol [Reference Example 1] 099109852 20 201034673 Example 1 Preparation of Compound 2 and Compound 2, 75.0 g of oxalic acid and 680 ml of THF were added to a 2-liter flask, followed by addition of 51.10 g of potassium carbonate at -19 ° C with stirring. 41. 〇 8 g of p-fluoroaniline and 75 ml: 〇^ which have been diluted with 75 ml of Thf at • _12.4 ° C or below have been added thereto. The reaction was carried out at -12.8 C to -14.43⁄4 for 1 hour, and 45 Torr of water was added. The liquid layer was separated at room temperature to separate the aqueous layer, 3 liters of water was added thereto, and liquid separation was again performed to separate the aqueous layer. An aqueous solution obtained by adding hydrazine, 600 ml of THF, and 2) 1.1 g of potassium carbonate in 308 ml of water was added to the organic layer to carry out liquid separation to separate the aqueous layer. 15 ml of water was added to the organic layer, and liquid separation was carried out to separate the aqueous layer. The organic layer was concentrated under reduced pressure until the residue was changed to 280 ml. 75 ml of MeCN was added to the concentrated solution, and the concentration operation was carried out 3 times under reduced pressure until the remaining amount of the solution became 280 ml. Then, add 600 ml of MeCN to it under cooling, then add 34.43 g of aniline and 75 ml of MeCN at -5.9 ° C or below, and add 47.79 g of hydrazine, diisopropylethyl at _ 9.2 ° C. Amine and 38 ml MeCN. Subsequently, 'the temperature was raised to room temperature, and after stirring for 12 hours, 48.42 g of 2-aminomethyl thiophene and 75 ml of MeCN were added to it at room temperature' followed by addition of 57.35 g of N,N-di Propylethylamine and 38 ml MeCN. The internal temperature was raised to 82.4 ° C, followed by stirring for 4.5 hours and 560 ml of water at 7 Torr. (: or higher internal temperature was added thereto, followed by cooling. It was confirmed that the crystal was precipitated at 65.8 in its internal temperature, stirred overnight at room temperature and filtered. The obtained crystal was washed with a solution of MeCN: water = 2:1. And then washed with 300 liters of water. The obtained crystal was dried under reduced pressure at 099109852 21 201034673 for 1 day to obtain crystals of 108.54 g of the free base of Compound a. NMR-DMSOd6: 4.71-4.73 (2H, 6.91-7.26 (5H, m), 7.37 (1H, dd, j=5.2Hz, 4.8Hz), 7.44-7'80<5H, m), 8.78 (2H, d, J=4.8Hz), 9.01, 9·05 ( 2H, m) · FAB: 389 Elemental analysis. Calculated for C2〇H17FNk: c, 6185; h, 4.41; N, 28.85; F, 4.89; Cl, 0, 〇〇. Found: (:, 6178; , 4.43; 1^, 28.81; F, 4.95; CI, 〇.〇〇〇 [Example 1] Preparation of "anhydrous salt of a compound having a ratio of a compound of 2 ··1 to fumaric acid" 414 liters Butanone and 23.00 kg of compound a were added to the reaction vessel 1 and dissolved at 65.0 ° C. After filtration, the mixture was transferred to the reaction vessel 2, followed by heating again. 6.90 kg of fumaric acid and 115 liters of ethanol were added to the reaction. Container 1 ' 58.3 C internal temperature dissolution 'moved to reaction vessel 2. After cooling, crystallization started at 54.2 hrs' and then stirred overnight at 〇 ° C. After filtration, the crystals were washed with 46 liters of ethanol and 30.34 kg. 1 salt crystal of the ratio of compound A to fumaric acid (ΙΠ crystal: wet) and 460 liters of ethanol were added to the reaction vessel at 2 ° in a suspension state at 52.4 ° C to 69.2. After stirring for 42 hours, 'cooling' and stirring at room temperature overnight. After filtration, the obtained crystals were washed with 46 liters of ethanol, and then dried at 6 TC under reduced pressure to obtain 20.97 kg of a compound having a compound of 2.1. An anhydrous salt crystal of the ratio of butenedioic acid" (work type). 099109852 22 201034673

Anhydrous _ crystal having a ratio of compound A to fumaric acid of 2: crystal) (type I NMR-DMSOd6: 4.71-4.73 (2H, rr〇, 6.64 (1H, s), 6.91-7.23 (5ii ( lHrdd, J=5.2Hz, 4.8Hz), 7.44-7.80(5H, m), 8.78(2H u 'called, 7.37 9.01-9.06 (2H, m), 13.06 (1H, br) ' , Js: 4.8 H2}, FAB+: 389 Elemental analysis. Calculated value of C2〇H17FN8.0.5C4H404: Γ c , 59.19 ; 4.29 ; N, 25.10 ; F, 4.26 ; 0, 7.17. Measured value · · c, 59 〇 9 · Good N , 25.19 ; F, 4.3 卜 ' 4 '36 ; endothermic onset temperature in DSC: about i9 〇 ° c The powder of Example 1 compound (type I crystal) is diffracted with a compound A of 1:1. The salt ratio of the ratio of fumaric acid to isobutanone to ethanol as a residual solvent = i 0.3) (type 111 crystal) is shown in Fig. 1. Crystal (compound A° '1 : 〇-0〇7 : NMR-DMSOd6 4.71 (2H, m), 6·64 (2H, s), 6·90_7.29 {5h, dd, · 8Hz, 4 - 8Hz), 7.57-7.81 (5h, m), 8 · 79 (23⁄4 (ijj 9.05-9.11 (2H, m), 13.09 (2H, br) ' ^ heart 4 ·卟2) ' ESI+:389

Elemental analysis. C2〇H17FN8,C4H4〇4.〇.i c4H80.0.〇〇7 H2〇 Calculated value: C, 56.67; H, 4.37; N, 21.66; F, 3 &0; Q measured value ···C, 56.56; H, 4.47; N, 21.68; F, 3.63. The endothermic onset temperature in DSC: about i6 〇 ° C, such as 6 〇. 〇 13.63 The powder of the compound of Example 1 (crystal of type III) X-ray diffraction is visible in [Example 2]

099109852 23 201034673

"Salt having a ratio of compound A to antibutanic acid of 2:1, hydrate of ratio of compound A to water of 2:1" (π-type crystal) Preparation of 3.0 g of compound ruthenium crystal, 120 ml of ethanol , and 3 ml of water was added to a 200 ml flask, heated to 76 ° C and dissolved. Subsequently, 448 mg of fumaric acid was added to its formazan, and it was dissolved at 8 (TC internal temperature. It was cooled and stirred at room temperature overnight. After filtration and dried at 40 ° C, 3.2 g of a compound having 2: oxime was obtained. A salt of a ratio of A to the antibutanic acid, which is a crystal of a hydrate having a ratio of the compound a to water of 2: (type 11 crystal). NMR-DMSOd6 4*72^4.74 (2Hr χη) c Cc riu . ' .(1H, s), 6.91-7.27 (5H, 7 37

{1H, dd, J=4.8Hz, 4.8Hz), 7 45_7 , 0 , called, /. W n /.43 /.81 (5H, m), 8.78 (2H, d, J=4 〇u7\ 9.02 -9.06 (2H, in}, 13.06 (1H, br} 4.8 Hz), FAB+: 389 兀 分析 analysis. QoHnFNs.OS C4H4 〇 4.0.5 Calculated value of HA: c 58.02 ; H, 4.43 ; N, 24.60; F , 4: ;, 8 78. Found: & % 2〇; H, 4.46; N, 24.77; F, 4.33. Endothermic onset temperature in DSC: about Example 2 compound (Π-type crystal The powder X-ray diffraction is shown in Fig. 2. [Example 3] There is a salt prepared at the beginning of the mouth for the ratio of vaporized hydrogen to 1 〇. 〇克 6' Kong Che, Du · fluorophenyl) 1,3,5·3 Mu _ml MeCN suspension (4) Add 6G gram B; and η 毫 milliform N=L, pick up fine Μ 2 reaction liquid, ο卩 to '(4) by distillation to find the residue Add 0. 5109109852 24 201034673 Add ethyl acetate. The organic layer is 5% water... Dehydrated with anhydrous sulphuric acid, washed with steamed 豕酉 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷彳. The remaining material is obtained by 10.8 g of light yellow amorphous type · methanol '〇: 〇 to 95 : 5) This amorphous type is dissolved in 200 ml of alcohol, and Add 2 grams of activated carbon, and add the heat to the blood for 1 minute. Rende, remove the activity by filtration through the diatomaceous earth pad. 'The residue obtained by removing the solvent by hunting distillation is used to soar. Ethanol solidified to collect solids by filtration', thereby obtaining 7.5 g of a colorless solid. This solid was heated and dissolved in 150 liters of 70% aqueous MeCN' and then allowed to cool at room temperature, and collected by sinking to obtain 7.08 g. Compound b. 7, 5 g of the obtained compound B was dissolved in 2 () () ml of alcohol and ml, 10 ml of 4 M hydrogen chloride / w solution was added to the towel, and then the solvent was removed by steaming crane. Ethanol was added to the obtained residue. Then, the mixture was stirred for 3 minutes to precipitate a solid. The solid was collected by suction and dried under reduced pressure. Then, it was suspended in MeCN, and heated under reflux for 10 minutes. The reaction solution was returned to room temperature to obtain a solid, and the solid was filtered, collected and dried. Drying under reduced pressure gave 7 25 g of a salt having a ratio of compound b to hydrogen chloride of 1:2 as a colorless crystal (crystal of type I). Crystal NMR of a salt having a ratio of compound b to hydrogen sulfide of 1:2 -DMS〇ds 4.78 (2H, m), 7.10 (2h, brs), 7.25 (2H, t, J=8.7Ηζ), 7·3~7.8 (6H, m), 8.85 (2Hf d, J=4.9Hz), 8.9-9.4 (1H, m), 10.45 (1H, brs) 10.88 (1H, brs) 'Elemental analysis. Calculated for HC1: C, 50.12; H, 3.79; 099109852 25 201034673 N, 23.38; F, 7·93; Cl, 14.79. Found: C, 50.03; H, 3.92; N, 23.33; F, 7.94; Cl, 14.84.

Endothermic onset temperature in DSC: about 160, 190 °C Powder X-ray diffraction of the compound of Example 3 (type I crystal) is shown in Figure 6. Compound B (free base) NMR-DMSOdg 4.70 (2H, d, J = 5.8 Hz), 7.00 (2H, m), 7.10 (2H, t, J = 8.7 Hz), 7.38 (1H, t, J=4.9 Hz), 7.57 (3H, brs), 7.80 (2H, brs>, 8.79 (2H, dr J=4.9Hz), 9.0-9.2 (2Hf m). FAB+: 407 [Example 4] Compound with 1:1 Preparation of a salt of B to the ratio of fumaric acid A solution of 285.6 mg of fumaric acid in 5 ml of ethanol was added to a solution of 1.0 g of Compound B in 50 ml of ethanol. Soon, the solid began to precipitate. Heating under reflux until the solid is completely dissolved, followed by stirring while standing to cool. When the internal temperature is lowered to 60 ° C, a very small amount of salt crystal having a ratio of compound B to fumaric acid of 1:1 is added thereto. Then, it was stirred at room temperature for 12 hours while standing to cool. The precipitated crystals were collected by filtration, washed with ethanol, and dried at 60 ° C under reduced pressure for 2 days to obtain 970 mg of "Compound B with fumaric acid." The salt of 1:1 is a colorless crystal (type I crystal). NMR-DMSOde 4.70 (2H, d, J = 5.7 Hz), 6.64 (2H, s), 7.00 (2H, m), 7.10 (2H, t, J=8.7Hz), 7·38 (1H, t, J=4.9Hz), 7.57 (3H, br s)r 7.80 (2H, brs), 8.80 (2H, d, J=4.9Hz), 9.0-9.2 (2H, m), 13.13 (2H, brs). 099109852 26 201034673 Alizarin analysis. Calculated value: c , 55.^ ; Η, 3.86, N, 21.45 ; F, 7·27. Found: c, 55 29 ; H, 4 〇 5 ; N, 2164 ; F, 7.32. - Endothermic onset temperature in DSC The effect of the acid addition salt of the compound of Example 4 (type 1 crystal) shown in the following test examples is shown in the following test examples. 测试 [Test Example 1 Stability] Evaluation of the property] Evaluation of the cleavage product during storage: Approximately 5 mg of the sample was weighed into a milliliter glass vial and tested under the following storage conditions. Condition 1: 70 ° C - relative humidity 75% _ open for 2 weeks Condition 2: 70. 〇 Protected from light - sealed 2 weeks Condition 3 : 25 ° C - D65 (3600 lux) - sealed - 2 weeks > gluten solution filled into the mass bottle including the stored sample to the mark 〇 The line is taken as the sample solution to quantify the compound A in the sample solution. Further, the detection of Compound A and Compound B was carried out using ultraviolet light of 266 nm and 254 nm, respectively, and the operation of the apparatus including the processing of the data was carried out according to the methods and procedures of the respective agricultural instructions. (Device: LC-1100 series, manufactured by Agilent) The results of these tests are shown in Table 1. Further, the quantitative value indicates the ratio of the residual amount of the compound A after the test to the compound A before the test. 099109852 27 201034673 [Table 1] Test conditions ------- Quantitative value (%) ---, - Example 1 ~--~-~_ Example 2 Example 4 Condition 1 ~-- 99 -- - 101 100 Condition 2 s---- 99 ----- 100 100 Condition 3 ---- 100 ------ 102 99 As shown in Table 1 'Obviously Compound A's anti-butadiene The acid salt has stability to high temperature and high humidity conditions, high temperature protection from light and light (conditions 1 to 3). [Test Example 3 Compound Α and/or Compound Β was used for the therapeutic effect of schizophrenia. The treatment of schizophrenia is confirmed by a research model of hyperactivity induced by ❹f-based (four). Methyl amphetamine is a psychostimulant known to cause symptoms similar to schizophrenia by increasing the transmission of dopaminergic neurons. The abnormal behavior of methyl amphetamines administered to animals is often used as a screening method for therapeutic drugs for schizophrenia (〇ka et al., 1993, Pharmacol. Exp. Ther., 264: 158_165, by reference Enter here). For δ, male ddY mice were placed in an activity monitoring device and methamphetamine was administered 3 minutes later. Immediately after the administration of thiophene amphetamine, the mouse will be returned to the hospital! As for the measurement of the activity, a Supermex sensor manufactured by Murmachi Co., Ltd. (Mur〇machi Kikai c〇, Ltd.) was used. The solvent or a plurality of diluted solutions obtained by diluting each test compound with a solvent of 099109852 28 201034673 was orally administered to a group of mice. As for the solvent, a 0.5% aqueous mercaptocellulose solution was used. Statistical analysis was performed between the solvent-administered group and the administered drug group using the Dunnett's test. Test compound Compound (1): anhydrous salt crystal having a ratio of compound A to fumaric acid of 2:1 Compound (2): crystal having a salt of compound B to hydrogen chloride of 1:2 (result) The results of inhibition of thiol amphetamine-induced hyperkinesia are shown in Table 2. The results in the table indicate the individual minimum effective dose of the compound administration group (the minimum dose shows a significant small amount of activity relative to the activity of the solvent administration group). Compounds A and B inhibit hyperactivity induced by thiol amphetamine. In other words, it was found that these two compounds have an effect of improving the symptoms of schizophrenia. Ο [Table 2] The lowest effective dose of the compound (mg/kg orally) (1) 0.1 (2) 0.03 Although the invention has been described in detail and with reference to specific examples thereof, it will be apparent to those skilled in the art that Many changes and modifications were made. 099109852 29 201034673 (industrial application) Providing (4-fluorophenyl)-,-phenyl-1^'-(pyrimidin-2-ylindenyl)-1,3,5-tris-2,4,6 - a triamine (compound A) fumarate and/or hydrazine, Ν'-贰(4-fluorophenyl)-Ν"-(pyrimidin-2-ylindenyl)-1,3,5- Tri-negative-2,4,6-triamine (compound printed fumarate and can be used as a drug or starting material with excellent stability and its novel crystals. [Simplified illustration] Example and clearer DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring to the drawings, in which: Figure 1 is a diagram showing a powder X-ray diffraction pattern of an anhydrous salt crystal (type I crystal) having a compound bismuth to maleic acid ratio of 2:1. To show a X-ray diffraction pattern of a salt crystal powder having a ratio of compound A to fumaric acid of 2:1, the salt is a hydrate having a compound A to water ratio of 2:1 (type II crystal) Figure 3 is a diagram showing a powder X-ray diffraction pattern of a crystal having a salt of a compound A to a ratio of 1:1 of a fumaric acid (Compound A to isobutanone belonging to a residual solvent to ethanol to water) Ratio = 1: 0.1 : 0.007 : 0.3) (111 crystal) Figure 4 shows the display The ratio of the compound A to the hydrogenation hydrogen is 1: 2 of the anhydrous salt crystal powder X-ray diffraction pattern. Fig. 5 is a salt crystal having a ratio of the compound B to the fumaric acid of 1:1 (type I) Fig. 6 is a view showing a powder X-ray diffraction pattern of a salt crystal (type I crystal) having a ratio of compound B to hydrochloric acid of 1:2. 099109852 30 201034673 Fig. 7 is a view A DSC graph having a ratio of compound A to fumaric acid of 2: an anhydrous salt crystal of yttrium (type I crystal). Fig. 8 is a graph showing a ratio of compound a to fumaric acid of 2: bismuth The DSC curve of the crystal body is a hydrate (type II crystal) having a compound A to water ratio of 2: 1. Figure 9 is a graph showing the ratio of compound A to fumaric acid: 丨:i The DSC curve of the salt crystal (Compound A is the ratio of isobutyrone to ethanol to water of residual solvent = 1: 0.007 : 〇 · 3) (Πΐ-type crystal). Figure 10 shows the compound Α gas The DSC curve of the hydrogen salt ratio of 1:2 anhydrous salt crystals. Figure 11 shows the salt crystals having a ratio of compound B to antibutanic acid of 1:1. DSC graph of the body (type I crystal) Fig. 12 is a DSC graph showing a salt crystal (type I crystal) having a ratio of compound b to hydrochloric acid of 1:2. Fig. 13 is a diagram showing the free base of the compound A. A plot of the powder X-ray diffraction pattern of the crystal. In the powder X-ray analysis using copper as the anode, '2 degrees of crystals' shows ridges such as about 7.7, about 19.5, about 21.8, and about 28.6. Figure 14 is a DSC chart showing the free-form alkali crystal of Compound A. The endothermic onset temperature in the DSC: about 185. (: 099109852 31

Claims (1)

201034673 VII. Scope of application: ι — a salt containing a compound of formula (I): And fumaric acid. 2. For the salt of claim 1, wherein Ri is H. * 3. For the salt of claim 2, wherein the ratio of the compound of formula (1) to fumaric acid is 2:1. 4. If you apply for the salt of item 1 of the patent scope, the rule 1 is 1? 5. The salt of claim 4, wherein the ratio of the compound of the formula (1) to fumaric acid is 1:1. 6. A medicinal composition comprising a compound of any one of the claims 5 to 5, comprising an effective amount of a compound according to any one of claims 1 to 0, and pharmaceutically acceptable Accepted carrier. 8. A pharmaceutical composition' comprises an effective amount of a crystal of the scope of application and a pharmaceutically acceptable carrier. Hall 099109852 32