WO2011007870A1 - 2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-n-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩、その結晶、その結晶多形およびそれらの製造方法 - Google Patents
2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-n-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩、その結晶、その結晶多形およびそれらの製造方法 Download PDFInfo
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- WO2011007870A1 WO2011007870A1 PCT/JP2010/062071 JP2010062071W WO2011007870A1 WO 2011007870 A1 WO2011007870 A1 WO 2011007870A1 JP 2010062071 W JP2010062071 W JP 2010062071W WO 2011007870 A1 WO2011007870 A1 WO 2011007870A1
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- pyridinyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P7/10—Antioedematous agents; Diuretics
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Definitions
- a compound that is an active ingredient of a pharmaceutical has few side effects, excellent storage stability of the compound under various conditions (light, temperature, humidity, etc.), and process control in the manufacturing stage of the pharmaceutical It is required to be easy to handle (easy to handle), etc., and if all these conditions are satisfied, it can be a pharmaceutical product.
- Patent Document 1 discloses 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (Trifluoromethoxy) phenyl] -3-pyridinecarboxamide exhibits a cell growth inhibitory action in a test system using a VEGF-induced HUVEC proliferation reaction evaluation system, and a tumor growth inhibitory action in a test system using a mouse tumor-bearing model
- the test system using the rat adjuvant arthritis model exhibits an inhibitory effect on foot edema
- the test system using the rat choroidal neovascularization model exhibits an inhibitory action on choroidal neovascularization
- Patent Document 1 discloses 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide. As a property, it is described that it is a pale yellow solid.
- Patent Document 1 discloses 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide. There is no specific description of benzenesulfonate, its crystal, its crystal polymorph and its production method, and 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide does not describe or suggest the problem of repeated mineralization resulting in mineral deposits in the stomach.
- the present inventors have shown that, in a rat one-week repeated oral dose toxicity test of Compound A (30 mg / kg), mineral deposition was observed in the stomach, whereas Compound A benzenesulfonate salt was repeated for four weeks in rats.
- the oral administration toxicity test (30 mg / kg)
- the present invention relates to a benzenesulfonate salt of 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide. It is.
- the present invention provides a solution of 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl in an organic solvent solution containing benzenesulfonic acid. ] 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl]-, which comprises the step of adding 3-pyridinecarboxamide A method for producing benzenesulfonate of 3-pyridinecarboxamide is also provided.
- the present invention also includes an organic containing 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide.
- benzenesulfonate of 4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide is also provided.
- the organic solvent is preferably an aprotic polar solvent or a cyclic ether.
- dimethyl sulfoxide or N, N-dimethylformamide is more preferable as the aprotic polar solvent, and tetrahydrofuran is more preferable as the cyclic ether.
- the d value of the powder X-ray diffraction pattern is 2-[[[2- [referred to as ⁇ -form having peaks characteristic of 4.4 angstrom, 3.8 angstrom and 2.3 angstrom. Also provided are crystals of the benzenesulfonate salt of (hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide.
- the present invention provides a good solvent solution containing benzenesulfonic acid and 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl. ] 2-[[[[2-[(hydroxyacetyl) amino]-] called ⁇ -form, comprising a step of adding 3-pyridinecarboxamide and a step of adding a poor solvent to the reaction solution. Also provided is a process for the preparation of benzenesulfonate crystals of 4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide.
- the poor solvent is substantially 2-[[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl]-at room temperature. It is preferably a solvent that does not dissolve benzenesulfonate of 3-pyridinecarboxamide, more preferably water, lower alkyl alcohol, lower alkyl ketone or lower alkyl carboxylic acid ester, and the solvent is water, ethanol, acetone or acetic acid. More preferred is ethyl, and particularly preferred is ethanol.
- the present invention provides a benzenesulfonate salt of Compound A, which is highly safe and excellent in storage stability, and useful as a pharmaceutical, its crystal, its crystal polymorph, and a method for producing them. Also provided is a medicament comprising at least one selected from the group consisting of a benzenesulfonate salt of Compound A, a crystal thereof and a crystal polymorph thereof.
- compound A can be manufactured based on the manufacturing method as described in US Patent Application Publication No. 2007/0149574, it is not limited to the manufacturing method.
- the “benzenesulfonate of compound A” means a compound formed from the above chemical structural formula (1) and benzenesulfonic acid.
- the constituent ratio of compound A and benzenesulfonic acid is preferably 1: 1 or 1: 2, and more preferably 1: 1.
- the “benzenesulfonate of compound A” is preferably a compound represented by the following chemical structural formula (2).
- Benzenesulfonate of Compound A is (1a) adding compound A to an organic solvent solution containing benzenesulfonic acid, or (1b) adding at least one of benzenesulfonic acid and its hydrate to an organic solvent solution containing Compound A; Can be manufactured.
- the temperature at the time of carrying out the above (1a) or (1b) is not particularly limited as long as salt formation proceeds, but it is preferably carried out under ice cooling or at room temperature, and 15-30 More preferably, it is carried out at ° C.
- the time for carrying out the above (1a) or (1b) is not particularly limited as long as it is sufficient for salt formation to proceed.
- the benzenesulfonic acid salt of Compound A produced in this operation can be used in a widely used processing method and / or purification method such as concentration under reduced pressure, crystallization with water or an organic solvent, filtration, washing, drying under reduced pressure, etc. It can be isolated and / or purified using techniques.
- the “organic solvent” in (1a) or (1b) is not particularly limited as long as it is an organic solvent capable of dissolving Compound A, but is preferably an aprotic polar solvent or a cyclic ether.
- the “aprotic polar solvent” is not particularly limited as long as it is a polar solvent having no proton-donating property.
- dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl examples include pyrrolidone and hexamethylphosphoramide. Of these, dimethyl sulfoxide or N, N-dimethylformamide is particularly preferable.
- the “cyclic ether” is not particularly limited as long as it is a cyclic ether containing 1 to 6 carbon atoms and 1 or 2 oxygen atoms.
- tetrahydrofuran is particularly preferred.
- the temperature at the time of addition of the poor solvent and the temperature after the addition at the time of carrying out the above (2a), (2b) or (2c) are not particularly limited as long as crystallization proceeds, It is preferable to carry out at a temperature of 15 to 30 ° C.
- the heating at the time of carrying out the above (2d) is not particularly limited as long as the heating is performed to such an extent that the benzenesulfonate of Compound A is dissolved completely in the lower alcohol, but the heating is performed at 40 to 70 ° C. It is preferable to warm, and it is more preferable to warm to 45 to 65 ° C.
- Cooling after heating is not particularly limited as long as crystallization proceeds, but it is preferably carried out under ice cooling or at room temperature (cooling), and is preferably carried out at 15 to 30 ° C. More preferred.
- the reaction time for carrying out the above (2a) or (2b) is not particularly limited as long as it is sufficient for the reaction to proceed.
- the crystallization time after the addition of the poor solvent in carrying out (2a), (2b), (2c) or (2d) is not particularly limited as long as crystallization proceeds. However, it is preferably carried out for 0.25 hours to 48 hours, more preferably 3 hours to 24 hours.
- the benzenesulfonate salt of the compound A which is called ⁇ -form, produced by the above reaction or the like is used in a commonly used treatment method and / or purification method, for example, vacuum concentration, crystallization with water or an organic solvent, It can be isolated and / or purified using techniques such as filtration, washing and drying under reduced pressure.
- the “good solvent” in the above (2a), (2b) or (2c) means “an organic solvent capable of dissolving the benzenesulfonate of Compound A”, and preferably an aprotic polar solvent. Particularly preferred is dimethyl sulfoxide or N, N-dimethylformamide.
- the “aprotic polar solvent” is not particularly limited as long as it is a polar solvent having no proton donating property.
- dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N -Methylpyrrolidone or hexamethylphosphoramide can be mentioned, among which dimethyl sulfoxide or N, N-dimethylformamide is preferred.
- the “lower alcohol” means an alcohol having 1 to 6 carbon atoms, and examples thereof include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and tert-butanol, and methanol or ethanol is particularly preferable. .
- the “lower alkyl ketone” means an alkyl ketone having 1 to 13 carbon atoms, preferably 1 to 7 carbon atoms, and examples thereof include acetone, methyl ethyl ketone, and diethyl ketone, and among these, acetone is preferable.
- the “lower alkyl carboxylic acid ester” means an alkyl carboxylic acid ester having 1 to 13 carbon atoms, preferably 1 to 7 carbon atoms, and examples thereof include ethyl acetate, methyl acetate and isopropyl acetate. Of these, ethyl acetate is preferred.
- the ratio of “good solvent” to “poor solvent” can be appropriately selected from the range of 10: 1 to 1:10, depending on the type of good solvent and poor solvent.
- the ratio thereof is preferably 3: 1 to 1: 1, more preferably 2: 1.
- the ratio is preferably in the range of 1: 3 to 1: 7, more preferably in the range of 1: 4 to 1: 6, and 1: 5. Is particularly preferred.
- the ratio thereof is preferably in the range of 1: 3 to 1: 7, more preferably in the range of 1: 4 to 1: 6, and 1: 5. It is particularly preferred.
- the ratio thereof is preferably in the range of 1: 2 to 1: 6, more preferably in the range of 1: 3 to 1: 5, and 1: 4. It is particularly preferred.
- the “lower alcohol” in (2d) means an alcohol having 1 to 6 carbon atoms, and examples thereof include methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol. Is preferred.
- time for carrying out the above (3a) or (3b) is not particularly limited as long as it is sufficient for salt formation to proceed.
- the crystals of the benzenesulfonate salt of the compound A, which is called ⁇ -type, produced by the above reaction or the like are used in a commonly used treatment method and / or purification method, for example, concentration under reduced pressure, filtration with water or an organic solvent, It can be isolated and / or purified using techniques such as washing and drying under reduced pressure.
- the compounds of the present invention may absorb water and become adsorbed water or become hydrates by being left in the atmosphere or recrystallized. Included in the invention.
- the compound of the present invention when used as a prophylactic or therapeutic agent for the above diseases, the compound of the present invention can be administered either orally or parenterally. If the dosage form is oral, tablets, capsules, granules, powders are parenteral, and injections, eye drops, nasal drops, percutaneous absorption agents, aerosols (“inhalants” And the like, and can be formulated using commonly used techniques.
- oral preparations such as tablets, capsules, granules, powders are lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate and other excipients, stearic acid, magnesium stearate Lubricants such as talc, binders such as starch, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose, low-substituted hydroxypropylcellulose, calcium citrate, hypromellose, hydroxymethylcellulose, macrogol, silicone Coating agents such as resins, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances can be used as necessary.
- Parenteral preparations such as injections and eye drops include isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, sodium phosphate, sodium hydrogen phosphate, sodium acetate , Buffering agents such as citric acid, glacial acetic acid, trometamol, surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil, stabilizers such as sodium citrate and sodium edetate , Benzalkonium chloride, paraben, benzotonium chloride, paraoxybenzoic acid ester, sodium benzoate, preservatives such as chlorobutanol, hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate, hydrogen carbonate Natri pH adjusting agents such as arm, a soothing agent such as benzyl alcohol, can be used
- the dosage of the compound of the present invention can be appropriately selected depending on symptoms, age, dosage form and the like.
- an oral preparation can be administered usually in an amount of 0.01 to 1000 mg, preferably 1 to 100 mg per day, in one or several divided doses.
- the eye drop can be administered at a concentration of usually 0.0001 to 10% (w / v), preferably 0.01 to 5% (w / v) once or divided into several times.
- Example 1 Method for producing benzenesulfonate of compound A> Tetrahydrofuran (2 mL) was added to compound A (200 mg) and stirred at room temperature. After confirming dissolution, benzenesulfonic acid monohydrate (85 mg) was added at the same temperature. After completion of salt formation, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the concentrated residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain benzenesulfonate of compound A in white (171 mg).
- benzenesulfonic acid monohydrate (207 mg) was added at the same temperature, and the mixture was further stirred for 1.25 hours. Subsequently, ethyl acetate (15 mL) was added and the mixture was further stirred for 3.5 hours. The precipitated solid was collected by filtration and dried under reduced pressure to obtain benzenesulfonate of Compound A in white (510 mg).
- Example 3 Production method 2 (ethanol / DMSO) of benzenesulfonate ( ⁇ crystal) of compound A> Dimethyl sulfoxide (2.0 mL) was added to Compound A (505 mg) and stirred at room temperature. After confirming dissolution, benzenesulfonic acid monohydrate (200 mg) was added at the same temperature, and the mixture was further stirred for 1.25 hours. Subsequently, ethanol (10 mL) was added and the mixture was further stirred for 2.5 hours. The precipitated solid was collected by filtration and dried under reduced pressure to obtain a benzenesulfonate salt of Compound A in white (482 mg).
- Example 4 Production method 3 of benzenesulfonate ( ⁇ crystal) of compound A (ethanol / DMSO)> Dimethyl sulfoxide (1650 g) was added to benzenesulfonic acid monohydrate (388 g) at room temperature (internal temperature 28 ° C.). Subsequently, Compound A (750 g) was added at the same temperature. After stirring at room temperature for 2.0 hours, the solution was filtered. Subsequently, ethanol (5938 g) was added to the filtrate and stirred at room temperature for 2.0 hours.
- Example 6 Method 5 for producing benzenesulfonate ( ⁇ crystal) of compound A (ethanol, standing at room temperature)> Ethanol (5 mL) was added to the benzenesulfonate salt of Compound A (99 mg), and the mixture was stirred at an external temperature of 85 ° C. for 3 minutes. After confirming dissolution, the solution was allowed to stand overnight at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to obtain benzenesulfonate of Compound A in white (66 mg).
- Example 8 Method 7 for producing benzenesulfonate ( ⁇ crystal) of Compound A (ethyl acetate / DMSO, stirring at room temperature)> Dimethyl sulfoxide (1.5 mL) was added to the benzenesulfonate salt of Compound A (1.0 g), and the mixture was stirred at an internal temperature of 50 ° C. for 6 minutes. After confirming dissolution, ethyl acetate (6.0 mL) was added. After stirring at room temperature for 4.5 hours, the precipitated solid was collected by filtration and dried under reduced pressure to obtain benzenesulfonate of Compound A in white (701 mg).
- Example 9 Production method 8 of benzenesulfonate ( ⁇ -crystal) of compound A (ethyl acetate / DMSO, ice-cooled standing)> Dimethyl sulfoxide (1.5 mL) was added to the benzenesulfonate salt of Compound A (1.0 g), and the mixture was stirred at an internal temperature of 50 ° C. for 6 minutes. After confirming dissolution, ethyl acetate (6.0 mL) was added.
- Example 10 Method 9 for producing benzenesulfonate ( ⁇ crystal) of compound A (acetone / DMSO, stirring at room temperature)> Dimethyl sulfoxide (1.5 mL) was added to the benzenesulfonate salt of Compound A (1.0 g), and the mixture was stirred at an internal temperature of 50 ° C. for 5 minutes. After confirming dissolution, acetone (7.0 mL) was added. After stirring at room temperature for 5.0 hours, the precipitated solid was collected by filtration and dried under reduced pressure to obtain benzenesulfonate of Compound A in white (629 mg).
- Example 11 Method 10 for producing benzenesulfonate ( ⁇ -crystal) of compound A (acetone / DMSO, standing on ice)> Dimethyl sulfoxide (1.5 mL) was added to the benzenesulfonate salt of Compound A (1.0 g), and the mixture was stirred at an internal temperature of 50 ° C. for 5 minutes. After confirming dissolution, acetone (7.0 mL) was added. After standing overnight with ice cooling (internal temperature 5 ° C.), the precipitated solid was collected by filtration and dried under reduced pressure to obtain benzenesulfonate of compound A in white (224 mg).
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Abstract
Description
本発明は、粉末X線回折パターンのd値として、8.1オングストローム、6.8オングストローム、4.1オングストロームおよび4.0オングストロームに特徴的なピークを有する、β型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶についても提供する。
本発明は、上述したいずれかのベンゼンスルホン酸塩、その結晶、そのα型と称される結晶およびそのβ型と称される結晶からなる群から選択される少なくとも一つを有効成分として含有する医薬についても提供する。
化合物Aのベンゼンスルホン酸塩は、
(1a)ベンゼンスルホン酸を含有する有機溶媒溶液に、化合物Aを添加すること、または、
(1b)化合物Aを含有する有機溶媒溶液に、ベンゼンスルホン酸およびその水和物の少なくともいずれかを添加すること、
により製造することができる。
α型と称される化合物Aのベンゼンスルホン酸塩の結晶は、
(2a)ベンゼンスルホン酸を含有する良溶媒溶液に、化合物Aを添加する工程と、それに続き、該反応溶液に貧溶媒を添加する工程、または、
(2b)化合物Aを含有する良溶媒溶液に、ベンゼンスルホン酸およびその水和物の少なくともいずれかを添加する工程と、それに続き、該反応溶液に貧溶媒を添加する工程、または、
(2c)化合物Aのベンゼンスルホン酸塩を含有する良溶媒溶液に、貧溶媒を添加すること、または、
(2d)加温した低級アルコールに化合物Aのベンゼンスルホン酸塩を添加して溶解する工程と、それに続き、低級アルコール溶液を冷却する工程、
により製造することができる。
このβ型と称される化合物Aのベンゼンスルホン酸塩の結晶は、
(3a)ベンゼンスルホン酸を含有する環状エーテル溶液に、化合物Aを添加すること、または、
(3b)化合物Aを含有する環状エーテル溶液に、ベンゼンスルホン酸およびその水和物の少なくともいずれかを添加すること、
により製造することができる。
<実施例1:化合物Aのベンゼンスルホン酸塩の製造方法>
化合物A(200mg)にテトラヒドロフラン(2mL)を加え室温で撹拌した。溶解を確認後、同温でベンゼンスルホン酸一水和物(85mg)を添加した。塩形成終了後、溶媒を減圧留去した。濃縮残留物に酢酸エチルを加え、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(171mg)。
1H-NMR(500MHz,DMSO-d6)
δ 4.02(s,2H),4.44(s,2H),7.17(dd,J=4.9,1.5Hz,1H),7.28-7.38(m,5H),7.58-7.60(m,2H),7.71(d,J=1.2Hz,1H),7.80-7.82(m,2H),7.99(dd,J=7.6,1.8Hz,1H),8.20(d,J=5.2Hz,2H),8.60(dd,J=4.9,1.8Hz,1H),10.66(s,1H)
<実施例2:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法1(酢酸エチル/DMSO)>
化合物A(503mg)にジメチルスルホキシド(2.0mL)を加え室温で撹拌した。溶解を確認後、同温でベンゼンスルホン酸一水和物(207mg)を添加し、さらに1.25時間撹拌した。続いて、酢酸エチル(15mL)を添加し、さらに3.5時間撹拌した。析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(510mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.05(s,2H),4.47(s,2H),7.28-7.38(m,7H),7.58-7.60(m,2H),7.81(d,J=9.2Hz,2H),8.01(dd,J=7.6,1.8Hz,1H),8.16(s,1H),8.24(d,J=5.5Hz,1H),8.59(dd,J=4.9,1.5Hz,1H),10.08(bs,1H),10.66(s,1H)
PXRD:
吸熱ピーク:206.2℃
<実施例3:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法2(エタノール/DMSO)>
化合物A(505mg)にジメチルスルホキシド(2.0mL)を加え室温で撹拌した。溶解を確認後、同温でベンゼンスルホン酸一水和物(200mg)を添加し、さらに1.25時間撹拌した。続いて、エタノール(10mL)を添加し、さらに2.5時間撹拌した。析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(482mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.07(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.58-7.60(m,2H),7.81(d,J=9.2Hz,2H),8.03(dd,J=7.6,1.8Hz,1H),8.15(s,1H),8.27(d,J=5.5Hz,1H),8.59(dd,J=4.9,1.8Hz,1H),10.32(bs,1H),10.67(s,1H)
PXRD:
吸熱ピーク:207.7℃
<実施例4:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法3(エタノール/DMSO)>
ベンゼンスルホン酸一水和物(388g)にジメチルスルホキシド(1650g)を室温で加えた(内温28℃)。続いて、同温で化合物A(750g)を添加した。室温で2.0時間撹拌した後、溶液をろ過した。続いて、ろ液にエタノール(5938g)を添加し、室温で2.0時間撹拌した。析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(820g)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.58-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(dd,J=7.8,1.8Hz,1H),8.14(s,1H),8.27(d,J=5.5Hz,1H),8.59(dd,J=5.0,1.8Hz,1H),10.40(bs,1H),10.66(s,1H)
PXRD:
化合物Aのベンゼンスルホン酸塩(99mg)にメタノール(3mL)を加えた後、外温65℃で4分間撹拌した。溶解を確認後、室温で一晩静置した。析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(50mg)。
1H-NMR(500MHz,DMSO-d6)
δ 4.12(s,2H),4.52(s,2H),7.30(dd,J=4.6,1.5Hz,1H),7.31-7.34(m,4H),7.38(d,J=8.6Hz,2H),7.47(d,J=5.8Hz,1H),7.60-7.62(m,2H),7.81-7.83(m,2H),8.05(dd,J=7.6,1.5Hz,1H),8.12(s,1H),10.68(s,1H),10.83(s,1H)
<実施例6:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法5(エタノール、室温静置)>
化合物Aのベンゼンスルホン酸塩(99mg)にエタノール(5mL)を加えた後、外温85℃で3分間撹拌した。溶解を確認後、室温で一晩静置した。析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(66mg)。
1H-NMR(500MHz,DMSO-d6)
δ 4.11(s,2H),4.52(s,2H),7.30(dd,J=4.6,2.4Hz,1H),7.31-7.34(m,4H),7.38(d,J=8.6Hz,2H),7.44(s,1H),7.60-7.61(m,2H),7.81-7.83(m,2H),8.05(d,J=7.6Hz,1H),8.12(s,1H),10.67(s,1H),10.83(bs,1H)
<実施例7:化合物のベンゼンスルホン酸塩(α晶)の製造方法6(酢酸エチル/DMSO、室温静置)>
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(1.5mL)を加えた後、内温50℃で11分間撹拌した。溶解を確認後、酢酸エチル(6.0mL)を加えた。室温で一晩静置した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(619mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.07(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(d,J=7.6Hz,1H),8.14(s,1H),8.26(d,J=5.5Hz,1H),8.58(dd,J=4.9,1.8Hz,1H),10.35(bs,1H),10.66(s,1H)
PXRD:
吸熱ピーク:207.2℃
<実施例8:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法7(酢酸エチル/DMSO、室温攪拌)>
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(1.5mL)を加えた後、内温50℃で6分間撹拌した。溶解を確認後、酢酸エチル(6.0mL)を加えた。室温で4.5時間撹拌した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(701mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(d,J=7.6Hz,1H),8.14(s,1H),8.27(d,J=5.8Hz,1H),8.59(dd,J=4.9,1.8Hz,1H),10.39(bs,1H),10.66(s,1H)
PXRD:
吸熱ピーク:209.2℃
<実施例9:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法8(酢酸エチル/DMSO、氷冷静置)>
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(1.5mL)を加えた後、内温50℃で6分間撹拌した。溶解を確認後、酢酸エチル(6.0mL)を加えた。氷冷(内温5℃)で一晩静置した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(227mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.30-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.02(d,J=6.4Hz,1H),8.14(s,1H),8.27(d,J=5.5Hz,1H),8.59(m,1H),10.36(bs,1H),10.66(s,1H)
PXRD:
吸熱ピーク:207.1℃
<実施例10:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法9(アセトン/DMSO、室温攪拌)>
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(1.5mL)を加えた後、内温50℃で5分間撹拌した。溶解を確認後、アセトン(7.0mL)を加えた。室温で5.0時間撹拌した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(629mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(dd,J=7.6,1.8Hz,1H),8.14(s,1H),8.27(d,J=5.8Hz,1H),8.59(dd,J=4.9,1.8Hz,1H),10.39(bs,1H),10.66(s,1H)
PXRD:
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(1.5mL)を加えた後、内温50℃で5分間撹拌した。溶解を確認後、アセトン(7.0mL)を加えた。氷冷(内温5℃)で一晩静置した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(224mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=8.9Hz,2H),8.03(dd,J=7.6,1.5Hz,1H),8.14(s,1H),8.27(d,J=5.8Hz,1H),8.59(dd,J=4.9,1.5Hz,1H),10.37(bs,1H),10.66(s,1H)
PXRD:
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(1.5mL)を加えた後、内温50℃で6分間撹拌した。溶解を確認後、水(0.8mL)を加えた。室温で1時間静置した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(928mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(dd,J=7.6,1.5Hz,1H),8.14(s,1H),8.27(d,J=5.8Hz,1H),8.59(dd,J=4.9,1.8Hz,1H),10.36(bs,1H),10.66(s,1H)
PXRD:
吸熱ピーク:205.5℃
<実施例13:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法12(水/DMSO、室温攪拌)>
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(1.5mL)を加えた後、内温50℃で5分間撹拌した。溶解を確認後、水(0.8mL)を加えた。室温で0.5時間撹拌した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(910mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(dd,J=7.6,1.8Hz,1H),8.14(s,1H),8.27(d,J=5.8Hz,1H),8.59(dd,J=4.9,1.5Hz,1H),10.40(bs,1H),10.66(s,1H)
PXRD:
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(1.5mL)を加えた後、内温50℃で5分間撹拌した。溶解を確認後、水(0.8mL)を加えた。氷冷(内温7℃)で一晩静置した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(927mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=8.9Hz,2H),8.03(dd,J=7.6,1.5Hz,1H),8.14(s,1H),8.27(d,J=5.5Hz,1H),8.59(dd,J=4.9,1.5Hz,1H),10.41(bs,1H),10.66(s,1H)
PXRD:
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(2.7mL)、エタノール(6.0mL)を加えた後、内温50℃で5分間撹拌した。室温で一晩静置した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(104mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(dd,J=7.6,1.8Hz,1H),8.14(s,1H),8.27(d,J=6.1Hz,1H),8.59(dd,J=4.9,1.8Hz,1H),10.39(bs,1H),10.66(s,1H)
TGA:
吸熱ピーク:210.1℃
<実施例16:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法15(エタノール/DMSO、室温攪拌)>
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(2.5mL)を加えた後、内温50℃で5分間撹拌した。溶解を確認後、エタノール(3.0mL)を加えた。室温で5.0時間撹拌した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(71mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(dd,J=7.6,1.5Hz,1H),8.14(s,1H),8.27(d,J=5.8Hz,1H),8.59(dd,J=4.9,1.8Hz,1H),10.40(bs,1H),10.66(s,1H)
TGA:
吸熱ピーク:210.7℃
<実施例17:化合物Aのベンゼンスルホン酸塩(α晶)の製造方法16(エタノール/DMSO、氷冷静置)>
化合物Aのベンゼンスルホン酸塩(1.0g)にジメチルスルホキシド(3.3mL)、エタノール(6.0mL)を加えた後、内温50℃で15分間撹拌した。氷冷(内温4℃)で一晩静置した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(301mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.29-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(d,J=7.6Hz,1H),8.14(s,1H),8.27(d,J=5.5Hz,1H),8.59(dd,J=4.9,1.8Hz,1H),10.37(bs,1H),10.66(s,1H)
PXRD:
化合物Aのベンゼンスルホン酸塩(4.0g)にジメチルスルホキシド(9.0mL)を加えた後、室温(内温25℃)で6分間撹拌した。溶解を確認後、エタノール(45mL)を加えた。室温で1.0時間撹拌した後、析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(3.3g)。
1H-NMR(500MHz,DMSO-d6):
δ 4.08(s,2H),4.49(s,2H),7.30-7.39(m,7H),7.59-7.61(m,2H),7.81(d,J=9.2Hz,2H),8.03(dd,J=7.6,1.5Hz,1H),8.14(s,1H),8.27(d,J=5.8Hz,1H),8.59(dd,J=4.9,1.5Hz,1H),10.40(bs,1H),10.67(s,1H)
PXRD:
化合物A(507mg)にテトラヒドロフラン(5.0mL)を加え室温で撹拌した。溶解を確認後、同温でベンゼンスルホン酸一水和物(202mg)を添加し、さらに1.5時間撹拌した。析出した固体をろ取、減圧乾燥すると、化合物Aのベンゼンスルホン酸塩が白色で得られた(591mg)。
1H-NMR(500MHz,DMSO-d6):
δ 4.05(s,2H),4.47(s,2H),7.27-7.38(m,7H),7.58-7.60(m,2H),7.80(d,J=9.2Hz,2H),8.02(dd,J=7.6,1.8Hz,1H),8.16(s,1H),8.24(d,J=5.5Hz,1H),8.59(dd,J=4.9,1.5Hz,1H),10.05(bs,1H),10.66(s,1H)
PXRD:
吸熱ピーク:205.5℃
なお、前記[製造例]中のPXRDの分析では、線源に銅放射線(40kV/40mA)を使用し、走査パラメータは、走査軸:2θ/θ、範囲:2.500-40.000°、走査モード:連続、サンプリング幅:0.020°、スキャンスピード:4.000°/分で、測定した。
(試験方法)
化合物Aのベンゼンスルホン酸塩、メタンスルホン酸塩およびp-トルエンスルホン酸塩について、40℃75%RH、60℃または光(1000lux/hr)の条件下に保存した後、化合物Aの各塩の含量をHPLCにて測定。保存前の含量を100%としたときの変化率を算出した。
(試験結果)
1)化合物A(フリー体)のラット1週間反復経口投与毒性試験
(試験・観察方法)
i)Crl:CD(SD)ラットに1%メチルセルロース液に懸濁した化合物A(10mL/kg(体重)、30mL/kg(体重))を1日1回、7日間経口投与した。
ii)前記投与完了後、該ラットをエーテル麻酔下、放血致死させた後、胃を摘出、それを10%中性緩衝ホルマリン水溶液で固定後、ヘマトキシリン・エオジン染色し標本を作製、胃の変化を病理組織学的に観察した。
(試験・観察方法)
i)Crl:CD(SD)ラットに1%メチルセルロース液に懸濁した化合物Aのベンゼンスルホン酸塩(10mL/kg(体重)、30mL/kg(体重))を1日1回、4週間経口投与した。
ii)前記投与完了後、該ラットをエーテル麻酔下、放血致死させた後、胃を摘出、それを10%中性緩衝ホルマリン水溶液で固定後、ヘマトキシリン・エオジン染色し標本を作製、胃の変化を病理組織学的に観察した。
化合物Aは1週間の反復経口投与により、胃に鉱質沈着が認められたのに対して、化合物Aのベンゼンスルホン酸塩は、4週間の反復経口投与でも、胃に鉱質沈着は認められなかった。
本発明化合物の代表的な製剤例を以下に示す。
本発明化合物 1mg
乳糖 66.4mg
トウモロコシデンプン 20mg
カルボキシメチルセルロースカルシウム 6mg
ヒドロキシプロピルセルロース 4mg
ステアリン酸マグネシウム 0.6mg
本発明化合物および/または添加物の種類および/または量を適宜変更することにより、所望の錠剤を得ることができる。また、これらの錠剤に、コーティング剤(たとえば、ヒプロメロース、マクロゴール、シリコーン樹脂などの通常のコーティング剤)を用いてコーティングを施し、目的とするコーティング錠を得ることができる。
本発明化合物 5mg
乳糖 145mg
本発明化合物と乳糖の混合比を適宜変更することにより、所望のカプセル剤を得ることができる。
本発明化合物 100mg
塩化ナトリウム 900mg
ポリソルベート80 200mg
ベンザルコニウム塩化物 5mg
水酸化ナトリウム 適量
塩酸 適量
滅菌精製水 適量
本発明化合物および/または添加物の種類および/または量を適宜変更することにより、所望の点眼剤を得ることができる。
Claims (30)
- 2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩。
- ベンゼンスルホン酸を含有する有機溶媒溶液に、2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドを添加する工程を含む、2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の製造方法。
- 2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドを含有する有機溶媒溶液に、ベンゼンスルホン酸およびその水和物の少なくともいずれかを添加する工程を含む、2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の製造方法。
- 有機溶媒が非プロトン性極性溶媒または環状エーテルである請求の範囲第2項または第3項に記載の製造方法。
- 非プロトン性極性溶媒がジメチルスルホキシドまたはN,N-ジメチルホルムアミドである請求の範囲第4項に記載の製造方法。
- 環状エーテルがテトラヒドロフランである請求の範囲第4項に記載の製造方法。
- 2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶。
- 粉末X線回折パターンのd値として、4.4オングストローム、3.8オングストロームおよび2.3オングストロームに特徴的なピークを有する、α型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶。
- ベンゼンスルホン酸を含有する良溶媒溶液に、2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドを添加する工程と、それに続き、該反応溶液に貧溶媒を添加する工程とを含む、α型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶の製造方法。
- 2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドを含有する良溶媒溶液に、ベンゼンスルホン酸およびその水和物の少なくともいずれかを添加する工程と、それに続き、該反応溶液に貧溶媒を添加する工程とを含む、α型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶の製造方法。
- 良溶媒が非プロトン性極性溶媒である請求の範囲第9項または第10項に記載の製造方法。
- 非プロトン性極性溶媒がジメチルスルホキシドまたはN,N-ジメチルホルムアミドである請求の範囲第11項に記載の製造方法。
- 貧溶媒が室温にて実質的に2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を溶解しない溶媒である請求の範囲第9項または第10項に記載の製造方法。
- 室温にて実質的に2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を溶解しない溶媒が水、低級アルキルアルコール、低級アルキルケトンまたは低級アルキルカルボン酸エステルである請求の範囲第13項に記載の製造方法。
- 室温にて実質的に2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を溶解しない溶媒が水、エタノール、アセトンまたは酢酸エチルである請求の範囲第13項に記載の製造方法。
- 室温にて実質的に2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を溶解しない溶媒がエタノールである請求の範囲第13項に記載の製造方法。
- 2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を含有する良溶媒溶液に、貧溶媒を添加する工程を含む、α型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶の製造方法。
- 良溶媒が非プロトン性極性溶媒である請求の範囲第17項に記載の製造方法。
- 非プロトン性極性溶媒が、ジメチルスルホキシドまたはN,N-ジメチルホルムアミドである請求の範囲第18項に記載の製造方法。
- 貧溶媒が室温にて実質的に2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を溶解しない溶媒である請求の範囲第17項に記載の製造方法。
- 室温にて実質的に2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を溶解しない溶媒が水、低級アルキルアルコール、低級アルキルケトンまたは低級アルキルカルボン酸エステルである請求の範囲第20項に記載の製造方法。
- 室温にて実質的に2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を溶解しない溶媒が水、エタノール、アセトンまたは酢酸エチルである請求の範囲第20項に記載の製造方法。
- 加温した低級アルコールに2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩を添加して溶解する工程と、それに続き、低級アルコール溶液を冷却する工程とを含む、α型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶の製造方法。
- 低級アルコールがメタノールまたはエタノールである請求の範囲第23項に記載の製造方法。
- 粉末X線回折パターンのd値として、8.1オングストローム、6.8オングストローム、4.1オングストロームおよび4.0オングストロームに特徴的なピークを有する、β型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶。
- ベンゼンスルホン酸を含有する環状エーテル溶液に、2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドを添加する工程を含む、β型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶の製造方法。
- 2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドを含有する環状エーテル溶液に、ベンゼンスルホン酸およびその水和物の少なくともいずれかを添加する工程を含む、β型と称される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミドのベンゼンスルホン酸塩の結晶の製造方法。
- 環状エーテルがテトラヒドロフランである請求の範囲第26項または第27項に記載の製造方法。
- 請求の範囲第1項、第7項、第8項または第25項のいずれかに記載のベンゼンスルホン酸塩、その結晶、そのα型と称される結晶およびそのβ型と称される結晶からなる群から選択される少なくとも一つを有効成分として含有する医薬。
- 請求の範囲第1項、第7項、第8項または第25項のいずれかに記載のベンゼンスルホン酸塩、その結晶、そのα型と称される結晶およびそのβ型と称される結晶からなる群から選択される少なくとも一つを有効成分として含有する経口または非経口剤。
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US13/384,590 US9029398B2 (en) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof |
KR1020127003670A KR101710740B1 (ko) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(히드록시아세틸)아미노]-4-피리디닐]메틸]티오]-n-[4-(트리플루오로메톡시)페닐]-3-피리딘카르복사미드의 벤젠술폰산염, 이의 결정, 이의 결정 다형 및 이들의 제조 방법 |
NZ597495A NZ597495A (en) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof |
MX2012000749A MX2012000749A (es) | 2009-07-17 | 2010-07-16 | Bencensulfonato de 2-[[[2-[(hidroxiacetil) amino]-4-piridinil]meti l] tio]-n-[4-(trifluorometox)fenil]-3-piridincarboxamida, cristal del mismo, cristal polimorfo de este y metodos para la produccion de estos. |
CN201080031652.1A CN102471273B (zh) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫代]-n-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺苯磺酸盐、其晶体、其多晶型物以及用于制备其的方法 |
EP10799928.6A EP2455368B1 (en) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof |
AU2010271746A AU2010271746B2 (en) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof |
CA2767992A CA2767992C (en) | 2009-07-17 | 2010-07-16 | 2 - [[[2 -[(hydroxyacetyl) amino]- 4 -pyridinyl] methyl] thio]- n -[4 - (trifluoromethoxy) phenyl]- 3 -pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof |
ES10799928.6T ES2554360T3 (es) | 2009-07-17 | 2010-07-16 | Bencenosulfonato de 2-[[[2-[(hidroxiacetil)amino]-4-piridinil]metil]tio]-n-[4 (trifluorometoxi)fenil]-3-piridincarboxamida, cristales del mismo, polimorfos del mismo y procesos para la producción del mismo |
BR112012001159A BR112012001159A2 (pt) | 2009-07-17 | 2010-07-16 | benzenossulfonato de 2 - [[[2 -[(hidroxiacetil) amino]- 4 -piridinil] metil] tio]- n -[4 - (trifluorometóxi) fenil]- 3 - piridinacarboxamida, cristal do mesmo, cristal polimorfo do mesmo, e métodos para produção do mesmo |
SG2012001467A SG177576A1 (en) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof |
EA201200146A EA019689B1 (ru) | 2009-07-17 | 2010-07-16 | Бензолсульфонат 2-[[[2-[(гидроксиацетил)амино]-4-пиридинил]метил]тио]-n-[4-(трифторметокси)фенил]-3-пиридинкарбоксамида, его кристаллы, его полиморфы и способы их получения |
IN1152DEN2012 IN2012DN01152A (en) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate crystal of same crystal polymorph thereof and methods for production thereof |
HK12108284.4A HK1167644A1 (en) | 2009-07-17 | 2012-08-23 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4- (trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof 2-[[[2-[()]-4-]]]-n-[4-()]-3- |
HK12108386.1A HK1167647A1 (en) | 2009-07-17 | 2012-08-28 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4- (trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof 2-[[[2-[()]-4-]]]-n-[4-()]-3- |
US14/686,577 US9359328B2 (en) | 2009-07-17 | 2015-04-14 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof |
US15/150,901 US9546140B2 (en) | 2009-07-17 | 2016-05-10 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof |
US15/368,028 US9902698B2 (en) | 2009-07-17 | 2016-12-02 | 2-[[[2-[(Hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof |
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US13/384,590 A-371-Of-International US9029398B2 (en) | 2009-07-17 | 2010-07-16 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof |
US14/686,577 Division US9359328B2 (en) | 2009-07-17 | 2015-04-14 | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof |
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EP (1) | EP2455368B1 (ja) |
JP (1) | JP5662719B2 (ja) |
KR (1) | KR101710740B1 (ja) |
CN (1) | CN102471273B (ja) |
AU (1) | AU2010271746B2 (ja) |
BR (1) | BR112012001159A2 (ja) |
CA (1) | CA2767992C (ja) |
EA (1) | EA019689B1 (ja) |
ES (1) | ES2554360T3 (ja) |
HK (2) | HK1167644A1 (ja) |
IN (1) | IN2012DN01152A (ja) |
MX (1) | MX2012000749A (ja) |
MY (1) | MY157122A (ja) |
NZ (1) | NZ597495A (ja) |
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JP2020117522A (ja) * | 2015-03-18 | 2020-08-06 | 参天製薬株式会社 | 徐放性医薬組成物 |
Families Citing this family (6)
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WO2013115201A1 (ja) | 2012-01-31 | 2013-08-08 | 参天製薬株式会社 | 非水性液体組成物 |
AU2014322111A1 (en) * | 2013-09-20 | 2016-04-07 | Santen Pharmaceutical Co., Ltd. | Polyethylene glycol-containing composition |
TW201609145A (zh) | 2013-12-25 | 2016-03-16 | 參天製藥股份有限公司 | 注射劑及形成緩釋(depot)之方法 |
CN108064171B (zh) * | 2015-03-17 | 2021-07-13 | 参天制药株式会社 | 含有多肽的医药组合物 |
JP2016175899A (ja) * | 2015-03-18 | 2016-10-06 | 参天製薬株式会社 | 医薬組成物の安定保存 |
WO2016178900A1 (en) * | 2015-05-01 | 2016-11-10 | Odin Biotech | Ocular implant for delivery of pyridinecarboxamide derivative |
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EP1717229A1 (en) * | 2004-02-17 | 2006-11-02 | Santen Pharmaceutical Co., Ltd. | Novel cyclic compound having 4-pyridylalkylthio group having (un)substituted amino introduced therein |
EP1864977A1 (en) * | 2005-03-31 | 2007-12-12 | Santen Pharmaceutical Co., Ltd. | Novel cyclic compound having pyrimidinylalkylthio group |
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ES2368153T3 (es) * | 2004-02-17 | 2011-11-14 | Santen Pharmaceutical Co., Ltd. | Nuevo compuesto cíclico que presenta un grupo 4-piridilalquiltio que presenta amino (no) sustituido introducido en el mismo. |
JP4626353B2 (ja) * | 2004-02-17 | 2011-02-09 | 参天製薬株式会社 | 置換又は無置換アミノ基を導入した4−ピリジルアルキルチオ基を有する新規環式化合物 |
JP4834441B2 (ja) | 2005-03-31 | 2011-12-14 | 参天製薬株式会社 | ピリミジニルアルキルチオ基を有する新規環式化合物 |
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Patent Citations (3)
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EP1717229A1 (en) * | 2004-02-17 | 2006-11-02 | Santen Pharmaceutical Co., Ltd. | Novel cyclic compound having 4-pyridylalkylthio group having (un)substituted amino introduced therein |
US20070149574A1 (en) | 2004-02-17 | 2007-06-28 | Santen Pharmaceutical Co., Ltd. | Novel cyclic compound having 4-pyridylalkylthio group having substituted or unsubstituted amino group introduced therein |
EP1864977A1 (en) * | 2005-03-31 | 2007-12-12 | Santen Pharmaceutical Co., Ltd. | Novel cyclic compound having pyrimidinylalkylthio group |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2020117522A (ja) * | 2015-03-18 | 2020-08-06 | 参天製薬株式会社 | 徐放性医薬組成物 |
US11090296B2 (en) | 2015-03-18 | 2021-08-17 | Santen Pharmaceutical Co., Ltd. | Sustained-release pharmaceutical composition |
Also Published As
Publication number | Publication date |
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KR20130025857A (ko) | 2013-03-12 |
MX2012000749A (es) | 2012-01-27 |
US20170081286A1 (en) | 2017-03-23 |
IN2012DN01152A (en) | 2015-04-10 |
SG177576A1 (en) | 2012-02-28 |
CA2767992A1 (en) | 2011-01-20 |
HK1167644A1 (en) | 2012-12-07 |
US20150291560A1 (en) | 2015-10-15 |
AU2010271746B2 (en) | 2014-07-03 |
US9902698B2 (en) | 2018-02-27 |
ES2554360T3 (es) | 2015-12-18 |
EA019689B1 (ru) | 2014-05-30 |
US9029398B2 (en) | 2015-05-12 |
CN102471273A (zh) | 2012-05-23 |
US20160251314A1 (en) | 2016-09-01 |
EP2455368A1 (en) | 2012-05-23 |
BR112012001159A2 (pt) | 2016-03-01 |
JP2011037844A (ja) | 2011-02-24 |
US9546140B2 (en) | 2017-01-17 |
EP2455368B1 (en) | 2015-09-16 |
US9359328B2 (en) | 2016-06-07 |
AU2010271746A1 (en) | 2012-02-02 |
JP5662719B2 (ja) | 2015-02-04 |
HK1167647A1 (en) | 2012-12-07 |
EP2455368A4 (en) | 2013-01-09 |
KR101710740B1 (ko) | 2017-02-27 |
US20120116088A1 (en) | 2012-05-10 |
CA2767992C (en) | 2017-03-21 |
CN102471273B (zh) | 2014-07-16 |
EA201200146A1 (ru) | 2012-06-29 |
NZ597495A (en) | 2013-08-30 |
MY157122A (en) | 2016-05-13 |
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