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WO2011158931A1 - Useful salts of indazole derivative - Google Patents

Useful salts of indazole derivative Download PDF

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Publication number
WO2011158931A1
WO2011158931A1 PCT/JP2011/063901 JP2011063901W WO2011158931A1 WO 2011158931 A1 WO2011158931 A1 WO 2011158931A1 JP 2011063901 W JP2011063901 W JP 2011063901W WO 2011158931 A1 WO2011158931 A1 WO 2011158931A1
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compound
toluenesulfonate
hydrochloride
phenyl
vinyl
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Japanese (ja)
Inventor
章一 勇
宣利 村松
信爾 谷村
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Kyowa Kirin Co Ltd
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Kyowa Hakko Kirin Co Ltd
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an acid salt of an indazole derivative useful for the treatment of abnormal cell growth such as cancer, ie (E) -N- ⁇ 5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2 -Relates to the acid salt of [2- (1H-indazol-3-yl) vinyl] phenyl ⁇ -3-methylthiophene-2-carboxamide.
  • IGF-1R type I insulin-like growth factor receptor
  • IGF-1R type I insulin-like Increased or activated growth factor ⁇ ⁇ receptor
  • amplification of a chromosome in which IGF-1R is present is known in breast cancer and melanoma [Genes Chromosomes Cancer, 11, 63 (1994)] . Therefore, IGF-1R is considered to be an effective target for cancer treatment, and IGF-1R inhibitors are considered useful as therapeutic agents for various cancers.
  • Compound (I) (E) -N- ⁇ 5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl ⁇ -3-methylthiophene-2 -Carboxamide (hereinafter sometimes referred to as Compound (I)) is known to exhibit a potent IGF-1R inhibitory action.
  • a compound is required to have good physical properties such as a physiologically acceptable solubility in the vicinity of neutrality.
  • the compound when the compound is handled as a pharmaceutical bulk powder, it has high stability (for example, It is a great advantage that the hygroscopicity is small.
  • the compound (I) also has good physical properties such as solubility and stability.
  • the object of the present invention is useful for the treatment of abnormal cell growth such as cancer through IGF-1R inhibitory action, and has a high dissolution rate in a solvent, a high solubility, a high in vivo absorbability, and a high stability.
  • Providing p-toluenesulfonate (para-toluenesulfonate) of compound (I), hydrochloride of compound (I), etc. with excellent physical properties such as low chargeability or with excellent quality It is in.
  • it is providing the pharmaceutical composition containing the p-toluenesulfonic acid salt of compound (I) or the hydrochloride of compound (I).
  • the present invention relates to the following (1) to (4).
  • (E) -N- ⁇ 5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl]- which is useful for the treatment of abnormal cell growth such as cancer and has excellent physical properties and quality, etc.
  • (E) -N- ⁇ 5- [4- (2 -Hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl ⁇ -3-methylthiophene-2-carboxamide hydrochloride, etc. are provided.
  • the horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%).
  • ⁇ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%), ⁇ ⁇ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change.
  • It represents the hygroscopicity of the hydrochloride of compound (I).
  • the horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%).
  • ⁇ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%)
  • ⁇ ⁇ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change. It represents the hygroscopicity of the p-toluenesulfonate salt of compound (I).
  • the horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%).
  • ⁇ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%)
  • ⁇ ⁇ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change.
  • the horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%).
  • ⁇ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%)
  • ⁇ ⁇ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change.
  • It represents the hygroscopicity of the hydrobromide salt of compound (I).
  • the horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%).
  • ⁇ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%)
  • ⁇ ⁇ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change.
  • the acid salt of compound (I) can be produced, for example, by the methods described in the examples and reference examples described later or a method analogous thereto.
  • Examples of the acid salt of the compound include hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide, and the like. Hydrochloride and p-toluenesulfonate are preferable, and p-toluenesulfonate is used. Is more preferable.
  • the acid salt of compound (I) may be a solvate or a hydrate.
  • the solvate examples include ethanol solvate, 2-propanol solvate, acetone solvate, polyethylene glycol solvate and the like, and preferably ethanol solvate and acetone solvate.
  • Acid salts of compound (I) are known in the art such as elemental analysis, polarized light microscopy, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), etc. It can be analyzed and characterized in any way.
  • the pharmaceutical composition of the present invention is a pharmaceutical composition for treating abnormal cell proliferation (eg, cancer, etc.) in mammals including humans, comprising a therapeutically effective amount of an acid salt of the compound (I) and a pharmaceutical agent.
  • the purpose of preparing a pharmaceutical composition is to facilitate administration of an acid salt of Compound (I) to mammals, including humans.
  • the therapeutic target of the pharmaceutical composition of the present invention includes hematopoietic tumors, solid cancers and the like.
  • a hematopoietic tumor refers to a tumor in, for example, blood cells, and specific pathological conditions based on these include leukemia such as chronic myelogenous leukemia and acute myeloid leukemia, myeloma such as multiple myeloma, lymphoma, etc. It is done.
  • solid cancer examples include breast cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, liver cancer, biliary tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, head and neck cancer, bone
  • examples include sarcoma, melanoma, and cancer caused by brain tumor.
  • the hydrochloride of the compound (I), the p-toluenesulfonate of the compound (I), the ethanesulfonate of the compound (I), and the compound (I) which are acid salts of the compound (I) used in the present invention The physical properties such as the stability of hydrobromide of I) will be specifically described by test examples.
  • Test Example 1 Compound (I), hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), hydrobromide of compound (I) Solubility Compound (I), Compound (I) hydrochloride, Compound (I) p-toluenesulfonate, Compound (I) ethanesulfonate, Compound (I) hydrobromide samples ( About 2 mg) was dissolved or suspended in 2 mL of phosphate buffer (PBS) and stirred in a 37 ° C. water bath for 1 hour and 24 hours.
  • PBS phosphate buffer
  • the filtrate was diluted 10-fold with 50% acetonitrile aqueous solution to obtain a sample solution.
  • a sample solution For each standard solution (see below), a certain amount was measured by liquid chromatography under the following conditions, and a calibration curve (peak area with respect to sample concentration) was prepared. The sample solution was also measured in the same manner as the standard solution, and the concentration of compound (I) in the sample solution was determined from the peak area of the sample solution using a calibration curve, and the solubility after 1 hour and 24 hours was calculated.
  • ⁇ Standard Solution Preparation Method 1 mg of each sample was accurately taken, and the total amount was exactly 10 mL with 50% acetonitrile aqueous solution. Further, the obtained solution was diluted at a common ratio of 10, and finally diluted to 1 ⁇ g / mL to obtain a standard solution.
  • JP1 JP 1 liquid
  • JP1 The first JP dissolution test solution
  • Table 1 shows the solubility of the compound (I) ethanol crystallized sample in PBS (after 1 hour and after 24 hours).
  • Table 3 shows the solubility (1 hour and 24 hours later) of the hydrochloride of compound (I) and p-toluenesulfonate of compound (I) in JP1.
  • the hydrochloride of compound (I), p-toluenesulfonate of compound (I), and ethanesulfonate of compound (I) are more soluble in PBS (24 hours) than the compound (I) ethanol crystallized sample. After) it was revealed that there was a significant improvement. That is, the hydrochloride of compound (I), the p-toluenesulfonate of compound (I), and the ethanesulfonate of compound (I) are more neutral (PBS) than the compound (I) ethanol crystallized sample. ) was improved.
  • DISMIC-13HP aqueous solvent, pore size 0.20 ⁇ m, ADVANTEC
  • the filtrate was diluted 10-fold with 30% acetonitrile aqueous solution to obtain a sample solution.
  • a certain amount was measured by liquid chromatography under the following conditions, and a calibration curve (peak area with respect to sample concentration) was prepared.
  • the above sample solution was also measured in the same manner as the standard solution, the concentration of compound (I) in the sample solution was determined from the peak area of the sample solution using a calibration curve, and the solubility after 1 hour and 24 hours was calculated.
  • ⁇ Standard Solution Preparation Method 1 mg of each sample was accurately taken, and the total amount was exactly 10 mL with 50% acetonitrile aqueous solution. Further, the obtained solution was diluted at a common ratio of 10, and finally diluted to 1 ⁇ g / mL to obtain a standard solution.
  • Table 5 shows the solubility of Compound (I) hydrochloride, Compound (I) p-toluenesulfonate, Compound (I) ethanesulfonate, and Compound (I) hydrobromide in FeSSIF. Show. In Table 5, N.T. means not measured.
  • the acid salt of the compound (I) (hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide) is obtained from the compound (I) ethanol crystal.
  • Solubility in the fed bile acid model solution (FeSSIF) was also superior to the chlorinated sample.
  • the high solubility in the fed bile acid model solution suggests that the acid salt of the compound (I) is highly soluble in the bile acid, and the in vivo absorbability of the acid salt of the compound (I) is high. Suggested to be higher.
  • Test Example 2 Compound (I), hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), hydrobromide of compound (I) Samples of hygroscopic compound (I), hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), hydrobromide of compound (I) (About 10 mg) was weighed, and the presence or absence of hygroscopicity was evaluated by measuring the increase and decrease of the sample weight by changing the relative humidity while maintaining the temperature at 25 ° C.
  • the compound (I) ethanol crystallized sample prepared in Reference Example 3 was used.
  • the hydrochloride of compound (I) p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), and hydrobromide of compound (I), respectively, Example 1 and 2.
  • Each salt obtained in Reference Examples 4 and 5 was used.
  • the hygroscopic measurement was performed under the following conditions. Measurement condition temperature: 25 °C Humidity: In the case of adsorption process, the relative humidity is increased by 10% from 0% to 90%, and in the case of desorption process, the relative humidity is decreased by 10% from 90% to 0%. It was.
  • Fig. 1 compound (I) ethanol crystallized sample
  • Fig. 2 hydrochloride of compound (I)
  • Fig. 3 compound (I) p- Toluene sulfonate
  • FIG. 4 ethane sulfonate of compound (I)
  • FIG. 5 hydrobromide of compound (I)
  • p-toluenesulfonic acid salt of compound (I) has better solubility in gastric juice due to better solubility in strong acid solution (JP1) than hydrochloride of compound (I). became.
  • the acid salt of the compound (I) hydroochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide, etc.
  • various pharmaceutical compositions are usually used. It is desirable to provide as.
  • those pharmaceutical compositions are used for mammals including humans.
  • the pharmaceutical composition of the present invention comprises an acid salt of the compound (I) (hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide, etc.) alone or as any other active ingredient It can be contained as a mixture with active ingredients for treatment.
  • these pharmaceutical compositions are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (eg, diluents, solvents, excipients, etc.). It is produced by any known method.
  • the administration route it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.
  • examples of the dosage form include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution, or a mixed solution of a saline solution and a glucose solution.
  • the dose and frequency of administration of the salt of Compound (I) should be determined according to the dosage form, patient age, body weight, and treatment although it varies depending on the nature or severity of symptoms, in the case of oral administration, the dose is usually 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 1000 mg, preferably 0.01 to 100 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.
  • -Boc represents a tert-butoxycarbonyl group (-COC (CH 3 ) 3 ).
  • ⁇ Step 1> (E) -N- ⁇ 5-hydroxymethyl-2- [2- (1H-indazol-3-yl) vinyl] phenyl ⁇ -3-methylthiophene-2-carboxamide obtained in Example 108 of WO2006 / 080450 ( Compound 4, 1.8 g, 4.6 mmol) was dissolved in N, N-dimethylformamide (18 mL), methanesulfonyl chloride (0.68 mL, 8.8 mmol) was added, and the mixture was stirred at room temperature for 4 hours.
  • -Boc represents a tert-butoxycarbonyl group (-COC (CH 3 ) 3 ).
  • Compound 5 (4.0 g, 6.7 mmol) obtained in Reference Example 1 was added to a mixture of methanol (0.16 L), water (32 mL), and concentrated hydrochloric acid (8 mL), and the mixture was stirred at 70 ° C. for 1.5 hours.
  • the reaction solution was cooled to 4 ° C, 4 mol / L aqueous sodium hydroxide solution (26 mL) was slowly added to adjust to pH 11, methanol was distilled off under reduced pressure, ethanol (40 mL) was added, Water (40 mL) was added dropwise.
  • Formulation example (tablet) A tablet having the following composition is prepared by a conventional method. Compound (I) hydrochloride (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, and 10% aqueous solution of hydroxypropylcellulose (120 g) is added thereto. The obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • Formulation example (tablet) A tablet having the following composition is obtained according to Example 3.
  • Formulation Compound (I) p-toluenesulfonate 20 mg Lactose 143.4 mg
  • Potato starch 30 mg Hydroxypropylcellulose 6 mg
  • Magnesium stearate 0.6 mg 200 mg
  • (E) -N- ⁇ 5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-) is useful for the treatment of abnormal cell proliferation such as cancer.
  • Indazol-3-yl) vinyl] phenyl ⁇ -3-methylthiophene-2-carboxamide acid salt is provided.

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Abstract

Provided are a p-toluenesulfonate of compound (I), a hydrochloride and other salts of said compound (I), and a pharmaceutical composition containing the p-toluenesulfonate, the hydrochloride, or the like of said compound (I) that have excellent physical properties and quality and that are useful in treating abnormal cell growth, such as cancer, by the action of inhibiting the type I insulin-like growth factor receptor (IGF-1R).

Description

インダゾール誘導体の有用な塩Useful salts of indazole derivatives

　本発明は、癌等の異常な細胞増殖の治療に有用なインダゾール誘導体の酸塩、すなわち、（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの酸塩に関する。 The present invention relates to an acid salt of an indazole derivative useful for the treatment of abnormal cell growth such as cancer, ie (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2 -Relates to the acid salt of [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide.

　多くの癌組織（例えば、肺癌、大腸癌、膵癌、乳癌、前立腺癌、肝癌、黒色腫、脳腫瘍、多発性骨髄腫、白血病等）で、I型インスリン様増殖因子受容体（type I insulin-like growth factor receptor、以下、IGF-1Rと表す）の発現の上昇または活性化がみられることが知られている［エンドクリン・レビューズ（Endocrine Reviews）、21巻、215頁（2000年）；ネイチャー・レビューズ・キャンサー（Nature Reviews Cancer）、4巻、505頁（2004年）]。また、稀ではあるが、乳癌及び黒色腫において、IGF-1Rが存在する染色体の増幅が知られている［ジーンズ・クロモソームズ・キャンサー（Genes Chromosomes Cancer）、11巻、63頁（1994年）］。故に、IGF-1Rは、癌治療の有効な標的と考えられ、IGF-1R阻害剤は様々な癌の治療薬として有用であると考えられる。 In many cancer tissues (eg lung cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, melanoma, brain tumor, multiple myeloma, leukemia, etc.) type I insulin-like growth factor receptor (type I insulin-like Increased or activated growth factor 発 現 receptor (hereinafter referred to as IGF-1R) is known [Endocrine Reviews, 21, 215 (2000); Nature・ Nature Reviews Cancer, Volume 4, 505 (2004)]. In rare cases, amplification of a chromosome in which IGF-1R is present is known in breast cancer and melanoma [Genes Chromosomes Cancer, 11, 63 (1994)] . Therefore, IGF-1R is considered to be an effective target for cancer treatment, and IGF-1R inhibitors are considered useful as therapeutic agents for various cancers.

　下記の式（I）で示される（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドは、強力なIGF-1R阻害作用を有することが報告されている（特許文献１）。 (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] represented by the following formula (I) Phenyl} -3-methylthiophene-2-carboxamide has been reported to have a strong IGF-1R inhibitory action (Patent Document 1).

Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001

国際公開第2006／080450号パンフレットInternational Publication No. 2006/080450 Pamphlet

　（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミド（以下、化合物（I）と表すこともある）は強力なIGF-1R阻害作用を示すことが知られている。
　一般に、化合物に関しては、生理的に許容される中性付近での溶解性等の物性が良好であることが求められ、更に、化合物を医薬原末として扱う場合には安定性が高いこと（例えば、吸湿性が小さいこと等）は大きな利点になる。従って、化合物（I）においても、溶解性、安定性等の物性が良好であることが望ましい。
　本発明の目的は、IGF-1R阻害作用を介して癌等の異常な細胞増殖の治療に有用で、溶媒への溶解速度が大きい、溶解度が大きい、生体内吸収性が高い、安定性が高い、帯電性が低い等の物性等の優れた、または品質の優れた化合物（I）のp-トルエンスルホン酸塩（パラ-トルエンスルホン酸塩）、化合物（I）の塩酸塩等を提供することにある。更に、化合物（I）のp-トルエンスルホン酸塩または化合物（I）の塩酸塩等を含有する医薬組成物を提供することにある。 (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 -Carboxamide (hereinafter sometimes referred to as Compound (I)) is known to exhibit a potent IGF-1R inhibitory action.
In general, a compound is required to have good physical properties such as a physiologically acceptable solubility in the vicinity of neutrality. Furthermore, when the compound is handled as a pharmaceutical bulk powder, it has high stability (for example, It is a great advantage that the hygroscopicity is small. Therefore, it is desirable that the compound (I) also has good physical properties such as solubility and stability.
The object of the present invention is useful for the treatment of abnormal cell growth such as cancer through IGF-1R inhibitory action, and has a high dissolution rate in a solvent, a high solubility, a high in vivo absorbability, and a high stability. Providing p-toluenesulfonate (para-toluenesulfonate) of compound (I), hydrochloride of compound (I), etc. with excellent physical properties such as low chargeability or with excellent quality It is in. Furthermore, it is providing the pharmaceutical composition containing the p-toluenesulfonic acid salt of compound (I) or the hydrochloride of compound (I).

　本発明は、以下の（１）～（４）に関する。
（１）（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドのp-トルエンスルホン酸塩及び（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの塩酸塩から選ばれる、一つの（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの酸塩。
（２）（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドのp-トルエンスルホン酸塩。
（３）（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの塩酸塩。
（４）癌の治療に有効な量の、（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドのp-トルエンスルホン酸塩及び（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの塩酸塩から選ばれる少なくとも一つの（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの酸塩、並びに薬学的に許容される担体を含有する医薬組成物。 The present invention relates to the following (1) to (4).
(1) (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methyl P-Toluenesulfonate of thiophene-2-carboxamide and (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazole-3- Yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide hydrochloride, one (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2 -[2- (1H-Indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide acid salt.
(2) (E) -N- {5- [4- (2-Hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methyl P-Toluenesulfonate of thiophene-2-carboxamide.
(3) (E) -N- {5- [4- (2-Hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methyl Thiophene-2-carboxamide hydrochloride.
(4) An effective amount of (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) for the treatment of cancer ) Vinyl] phenyl} -3-methylthiophene-2-carboxamide p-toluenesulfonate and (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [ At least one (E) -N- {5- [4- (2-hydroxyacetyl) selected from the hydrochloride of 2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide ) Contains piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide acid salt and a pharmaceutically acceptable carrier Pharmaceutical composition.

　本発明により、癌等の異常な細胞増殖の治療に有用で、物性、品質等の優れた、（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドのp-トルエンスルホン酸塩、及び（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの塩酸塩、等が提供される。 According to the present invention, (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl]-, which is useful for the treatment of abnormal cell growth such as cancer and has excellent physical properties and quality, etc. P-Toluenesulfonate of 2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide, and (E) -N- {5- [4- (2 -Hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide hydrochloride, etc. are provided.

化合物（I）エタノール結晶化試料の吸湿性を表す。横軸は相対湿度（Relative humidity、％）を表し、縦軸は重量変化（Weight change、％）を表す。◆は吸着過程（adsorption、相対湿度0％から90％まで10％毎に上昇）における重量変化を表し、■は脱着過程（desorption、相対湿度を90％から0%まで10%毎に降下）における重量変化を表す。It represents the hygroscopicity of the compound (I) ethanol crystallized sample. The horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%). ◆ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%), ■ ■ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change. 化合物（I）の塩酸塩の吸湿性を表す。横軸は相対湿度（Relative humidity、％）を表し、縦軸は重量変化（Weight change、％）を表す。◆は吸着過程（adsorption、相対湿度0％から90％まで10％毎に上昇）における重量変化を表し、■は脱着過程（desorption、相対湿度を90％から0%まで10%毎に降下）における重量変化を表す。It represents the hygroscopicity of the hydrochloride of compound (I). The horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%). ◆ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%), ■ ■ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change. 化合物（I）のp-トルエンスルホン酸塩の吸湿性を表す。横軸は相対湿度（Relative humidity、％）を表し、縦軸は重量変化（Weight change、％）を表す。◆は吸着過程（adsorption、相対湿度0％から90％まで10％毎に上昇）における重量変化を表し、■は脱着過程（desorption、相対湿度を90％から0%まで10%毎に降下）における重量変化を表す。It represents the hygroscopicity of the p-toluenesulfonate salt of compound (I). The horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%). ◆ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%), ■ ■ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change. 化合物（I）のエタンスルホン酸塩の吸湿性を表す。横軸は相対湿度（Relative humidity、％）を表し、縦軸は重量変化（Weight change、％）を表す。◆は吸着過程（adsorption、相対湿度0％から90％まで10％毎に上昇）における重量変化を表し、■は脱着過程（desorption、相対湿度を90％から0%まで10%毎に降下）における重量変化を表す。It represents the hygroscopicity of the ethanesulfonate salt of compound (I). The horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%). ◆ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%), ■ ■ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change. 化合物（I）の臭化水素酸塩の吸湿性を表す。横軸は相対湿度（Relative humidity、％）を表し、縦軸は重量変化（Weight change、％）を表す。◆は吸着過程（adsorption、相対湿度0％から90％まで10％毎に上昇）における重量変化を表し、■は脱着過程（desorption、相対湿度を90％から0%まで10%毎に降下）における重量変化を表す。It represents the hygroscopicity of the hydrobromide salt of compound (I). The horizontal axis represents relative humidity (Relative humidity,%), and the vertical axis represents weight change (Weight change,%). ◆ represents the weight change in the adsorption process (adsorption, relative humidity increases from 0% to 90% every 10%), ■ ■ represents the desorption process (desorption, relative humidity decreases from 90% to 0% every 10%) Represents weight change.

　（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドは、公知の方法、例えば国際公開第2006／080450号（WO2006／080450）パンフレット記載の方法またはそれに準じた方法で得ることができる。また、本明細書の参考例に記載した方法によっても製造することができる。
　化合物（I）の結晶は、例えば、後述の参考例記載の方法またはそれに準じた方法によって製造することができる。
　化合物（I）の酸塩は、例えば、後述の実施例、参考例記載の方法またはそれらに準じた方法によって製造することができる。化合物の酸塩としては、塩酸塩、p-トルエンスルホン酸塩、エタンスルホン酸塩、臭化水素酸塩等が挙げられ、塩酸塩、p-トルエンスルホン酸塩が好ましく、p-トルエンスルホン酸塩がより好ましい。
　化合物（I）の酸塩は、溶媒和物であってもよく、水和物であってもよい。溶媒和物としては、例えばエタノール和物、2-プロパノール和物、アセトン和物、ポリエチレングリコール和物等が挙げられ、好ましくは、エタノール和物、アセトン和物等が挙げられる。
　化合物（I）の酸塩は、元素分析、偏光顕微鏡観察、粉末Ｘ線回折（PXRD）、示差走査熱量測定（DSC）、熱重量分析（thermal gravimetric analysis: TGA）等の当技術分野で公知の任意の方法で分析、特徴づけすることができる。
　本発明の医薬組成物は、ヒトを含む哺乳動物における異常な細胞増殖（例えば、癌等）を治療する医薬組成物であって、治療に有効な量の化合物（I）の酸塩及び薬学的に許容される一種またはそれ以上の担体を含む。医薬組成物を調製する目的は、ヒトを含む哺乳動物に対する、化合物（I）の酸塩の投与を容易にすることである。
　本発明の医薬組成物の治療対象には造血器腫瘍、固形癌等が含まれる。
　造血器腫瘍は、例えば血球細胞等における腫瘍を指し、これらに基づく病態としては具体的には慢性骨髄性白血病、急性骨髄性白血病等の白血病、多発性骨髄腫等の骨髄腫、リンパ腫等が挙げられる。
　固形癌としては、例えば乳癌、子宮体癌、子宮頚癌、前立腺癌、膀胱癌、腎癌、胃癌、食道癌、肝癌、胆道癌、大腸癌、直腸癌、膵癌、肺癌、頭頚部癌、骨肉腫、メラノーマ、脳腫瘍による癌等が挙げられる。
　以下、本発明で用いられる化合物（I）の酸塩である、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、及び化合物（I）の臭化水素酸塩の安定性等の物性について試験例により具体的に説明する。
　試験例１：化合物（I）、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩の溶解度
　化合物（I）、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩の各試料（約2 mg）を、リン酸塩緩衝液（PBS）2mLに溶解または懸濁させ、37℃の水浴中で1時間及び24時間撹拌した。これをDISMIC-13HP（水系溶媒、孔径0.20μm, ADVANTEC）で濾過後、濾液を50％アセトニトリル水溶液で10倍希釈し、試料溶液とした。各標準溶液（下記参照）一定量につき、下記条件の液体クロマトグラフィーで測定し、（試料濃度に対するピーク面積の）検量線を作成した。前述の試料溶液も標準溶液と同様に測定し、検量線を用いて試料溶液のピーク面積から試料溶液中の化合物（I）の濃度を求め、1時間後及び24時間後の溶解度を算出した。
　＜標準溶液調製法＞　各試料 1 mgを正確に採り、50％アセトニトリル水溶液で正確に総量を10mLとした。さらに、得られた溶液を用いて公比10で希釈し、最終的に1μg/mLになるまで希釈を行い、標準溶液とした。
　＜液体クロマトグラフィーの測定条件＞
測定装置：LC-20A
分離カラム：XBridge C18, 150 mm×4.6 mm, 5 μm
カラム温度：40℃
移動相：（A）10 mmol/L 酢酸アンモニウム水溶液
　　 　 （B）アセトニトリル
グラジエント条件：（B）10％／（A）90％　→　（B）70％／（A）30％（30分間で（B）濃度を10％から70％に上昇、なお、％は体積％）
液流量：1.0 mL/分
検出波長：265 nm
注入量：10 μL
化合物保持時間：約19分
 
　なお、PBSの組成は以下の通りである。
　塩化カリウム（KCl）0.27mmol/L、リン酸二水素カリウム（KH2PO4）0.15mmol/L、塩化ナトリウム（NaCl）13.69mmol/L、リン酸水素二ナトリウム（Na2HPO4）0.81mmol/L
 
　化合物（I）としては、化合物（I）エタノール結晶化試料（参考例３で調製）を用いた。化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩としては各々、後記の実施例１及び２、参考例４及び５で得られる各々の酸塩を用いた。
　更に、化合物（I）の塩酸塩及び化合物（I）のp-トルエンスルホン酸塩については、上記と同様の方法を用いて、日局溶出試験第1液（JP1）2mLに対する1時間後及び24時間後の溶解度も算出した。
　なお、日局溶出試験第1液（以下、JP1と表すこともある）は、塩化ナトリウム2.0gを塩酸7.0mL及び水に溶解して1000mLにした溶液である（JP1は無色透明で、そのpHは約1.2である）。
　化合物（I）エタノール結晶化試料のPBSへの溶解度（1時間後、24時間後）を第１表に示す。 (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 Carboxamide can be obtained by a known method, for example, the method described in the pamphlet of International Publication No. 2006/080450 (WO2006 / 080450) or a method analogous thereto. Moreover, it can manufacture also by the method described in the reference example of this specification.
The crystal of compound (I) can be produced, for example, by the method described in Reference Examples described later or a method analogous thereto.
The acid salt of compound (I) can be produced, for example, by the methods described in the examples and reference examples described later or a method analogous thereto. Examples of the acid salt of the compound include hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide, and the like. Hydrochloride and p-toluenesulfonate are preferable, and p-toluenesulfonate is used. Is more preferable.
The acid salt of compound (I) may be a solvate or a hydrate. Examples of the solvate include ethanol solvate, 2-propanol solvate, acetone solvate, polyethylene glycol solvate and the like, and preferably ethanol solvate and acetone solvate.
Acid salts of compound (I) are known in the art such as elemental analysis, polarized light microscopy, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), etc. It can be analyzed and characterized in any way.
The pharmaceutical composition of the present invention is a pharmaceutical composition for treating abnormal cell proliferation (eg, cancer, etc.) in mammals including humans, comprising a therapeutically effective amount of an acid salt of the compound (I) and a pharmaceutical agent. One or more carriers which are acceptable. The purpose of preparing a pharmaceutical composition is to facilitate administration of an acid salt of Compound (I) to mammals, including humans.
The therapeutic target of the pharmaceutical composition of the present invention includes hematopoietic tumors, solid cancers and the like.
A hematopoietic tumor refers to a tumor in, for example, blood cells, and specific pathological conditions based on these include leukemia such as chronic myelogenous leukemia and acute myeloid leukemia, myeloma such as multiple myeloma, lymphoma, etc. It is done.
Examples of solid cancer include breast cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, liver cancer, biliary tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, head and neck cancer, bone Examples include sarcoma, melanoma, and cancer caused by brain tumor.
Hereinafter, the hydrochloride of the compound (I), the p-toluenesulfonate of the compound (I), the ethanesulfonate of the compound (I), and the compound (I) which are acid salts of the compound (I) used in the present invention The physical properties such as the stability of hydrobromide of I) will be specifically described by test examples.
Test Example 1: Compound (I), hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), hydrobromide of compound (I) Solubility Compound (I), Compound (I) hydrochloride, Compound (I) p-toluenesulfonate, Compound (I) ethanesulfonate, Compound (I) hydrobromide samples ( About 2 mg) was dissolved or suspended in 2 mL of phosphate buffer (PBS) and stirred in a 37 ° C. water bath for 1 hour and 24 hours. After filtering this with DISMIC-13HP (aqueous solvent, pore size 0.20 μm, ADVANTEC), the filtrate was diluted 10-fold with 50% acetonitrile aqueous solution to obtain a sample solution. For each standard solution (see below), a certain amount was measured by liquid chromatography under the following conditions, and a calibration curve (peak area with respect to sample concentration) was prepared. The sample solution was also measured in the same manner as the standard solution, and the concentration of compound (I) in the sample solution was determined from the peak area of the sample solution using a calibration curve, and the solubility after 1 hour and 24 hours was calculated.
<Standard Solution Preparation Method> 1 mg of each sample was accurately taken, and the total amount was exactly 10 mL with 50% acetonitrile aqueous solution. Further, the obtained solution was diluted at a common ratio of 10, and finally diluted to 1 μg / mL to obtain a standard solution.
<Measurement conditions for liquid chromatography>
Measuring device: LC-20A
Separation column: XBridge C18, 150 mm x 4.6 mm, 5 μm
Column temperature: 40 ° C
Mobile phase: (A) 10 mmol / L ammonium acetate aqueous solution (B) Acetonitrile gradient conditions: (B) 10% / (A) 90% → (B) 70% / (A) 30% ((B) in 30 minutes Concentration increased from 10% to 70%, where% is volume%)
Liquid flow rate: 1.0 mL / min Detection wavelength: 265 nm
Injection volume: 10 μL
Compound retention time: about 19 minutes
The composition of PBS is as follows.
Potassium chloride (KCl) 0.27 mmol / L, Potassium dihydrogen phosphate (KH 2 PO 4 ) 0.15 mmol / L, Sodium chloride (NaCl) 13.69 mmol / L, Disodium hydrogen phosphate (Na 2 HPO 4 ) 0.81 mmol / L

As compound (I), compound (I) ethanol crystallized sample (prepared in Reference Example 3) was used. As the hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), and hydrobromide of compound (I), respectively, Example 1 and 2. Each acid salt obtained in Reference Examples 4 and 5 was used.
Further, for the hydrochloride of compound (I) and p-toluenesulfonate of compound (I), using the same method as described above, 1 hour after 2 mL of JP 1 liquid (JP1) and 24 The solubility after time was also calculated.
The first JP dissolution test solution (hereinafter sometimes referred to as JP1) is a solution prepared by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water to 1000 mL (JP1 is colorless and transparent, its pH Is about 1.2).
Table 1 shows the solubility of the compound (I) ethanol crystallized sample in PBS (after 1 hour and after 24 hours).

Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002

　化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩のPBSへの溶解度（1時間後、24時間後）を第２表に示す。 Solubility of Compound (I), p-toluenesulfonate of Compound (I), ethanesulfonate of Compound (I), hydrobromide of Compound (I) in PBS (after 1 hour, 24 hours later) is shown in Table 2.

Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003

　化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩のJP1への溶解度（1時間後、24時間後）を第３表に示す。 Table 3 shows the solubility (1 hour and 24 hours later) of the hydrochloride of compound (I) and p-toluenesulfonate of compound (I) in JP1.

Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004

（１）PBSに対する溶解度（第１表、第２表）
　化合物（I）エタノール結晶化試料の1時間後の溶解度は、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩の1時間後の溶解度に比べて、同程度または若干小さかった。
　化合物（I）エタノール結晶化試料の24時間後の溶解度は、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩の24時間後の溶解度よりも大幅に低下していたことが明らかになった。
　以上より、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩は、化合物（I）エタノール結晶化試料よりもPBSに対する溶解度（24時間後）が大幅に向上していることが明らかになった。
　すなわち、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩は、化合物（I）エタノール結晶化試料よりも、中性条件下（PBS）の溶解度が向上していた。
（２）JP1に対する溶解度（第３表）
　化合物（I）の塩酸塩と化合物（I）のp-トルエンスルホン酸塩では、1時間後においても24時間後においても、化合物のp-トルエンスルホン酸塩の溶解度の方が大きいことが明らかになった。
　すなわち、化合物（I）のp-トルエンスルホン酸塩は、化合物（I）の塩酸塩よりも、強酸条件下（JP1）の溶解度が向上していた。 (1) Solubility in PBS (Tables 1 and 2)
The solubility of the compound (I) ethanol crystallized sample after 1 hour is as follows: hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), compound (I) As compared with the solubility of hydrobromide after 1 hour, it was comparable or slightly smaller.
The solubility of the compound (I) ethanol crystallized sample after 24 hours is the compound (I) hydrochloride, compound (I) p-toluenesulfonate, compound (I) ethanesulfonate after 24 hours. It became clear that it was significantly lower than the solubility.
From the above, the hydrochloride of compound (I), p-toluenesulfonate of compound (I), and ethanesulfonate of compound (I) are more soluble in PBS (24 hours) than the compound (I) ethanol crystallized sample. After) it was revealed that there was a significant improvement.
That is, the hydrochloride of compound (I), the p-toluenesulfonate of compound (I), and the ethanesulfonate of compound (I) are more neutral (PBS) than the compound (I) ethanol crystallized sample. ) Was improved.
(2) Solubility in JP1 (Table 3)
It is clear that the solubility of the p-toluenesulfonate salt of the compound (I) and the p-toluenesulfonate salt of the compound (I) is greater after 1 and 24 hours. became.
That is, the p-toluenesulfonate salt of Compound (I) had improved solubility under strong acid conditions (JP1) than the hydrochloride salt of Compound (I).

　化合物（I）の酸塩（塩酸塩、p-トルエンスルホン酸塩、エタンスルホン酸塩、臭化水素酸塩）の摂食胆汁酸モデル液（以下、FeSSIFと表すこともある）に対する溶解度を測定した。
　化合物（I）、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩の各試料（約2 mg）を摂食胆汁酸モデル液（FeSSIF）2mLに溶解または懸濁させ、37℃の水浴中で1時間及び24時間撹拌した。これをDISMIC-13HP（水系溶媒、孔径0.20μm、ADVANTEC）で濾過後、濾液を30％アセトニトリル水溶液で10倍希釈し、試料溶液とした。各標準溶液（下記参照）一定量につき、下記条件の液体クロマトグラフィーで測定し、（試料濃度に対するピーク面積の）検量線を作成した。前述の試料溶液も標準溶液と同様に測定し、検量線を用いて試料溶液のピーク面積から試料溶液中の化合物（I）濃度を求め、1時間後及び24時間後の溶解度を算出した。
　＜標準溶液調製法＞　各試料 1 mgを正確に採り、50％アセトニトリル水溶液で正確に総量を10mLとした。さらに、得られた溶液を用いて公比10で希釈し、最終的に1μg/mLになるまで希釈を行い、標準溶液とした。
　＜液体クロマトグラフィーの測定条件＞
測定装置：LC-20A
分離カラム：XBridge C18, 150 mm×4.6 mm, 5 μm
カラム温度：40℃
移動相：（A）10 mmol/L 酢酸アンモニウム水溶液
　   　 （B）アセトニトリル
グラジエント条件：（B）10％／（A）90％　→　（B）70％／（A）30％（30分間で（B）濃度を10％から70％に上昇、なお、％は体積％）
液流量：1.0 mL/分
検出波長：265 nm
注入量：10 μL
　化合物保持時間：約19分
 
　摂食胆汁酸モデル液（FeSSIF）の組成は、以下の通りである。
　蒸留水1000mLに、タウロコール酸ナトリウム（Sodium taurocholate）15mmol/L、レシチン（Lecithin）3.75 mmol/L、水酸化ナトリウム（NaOH）4.04g、氷酢酸（Glacial Acetic Acid）8.65g及び塩化ナトリウム（NaCl）11.874gを含有する。
　化合物（I）としては、化合物（I）エタノール結晶化試料（参考例３で調製）を用いた。化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩としては各々、後記の実施例１及び２、参考例４及び５で得られる各々の塩を用いた。
　化合物（I）エタノール結晶化試料のFeSSIF への溶解度（1時間後、24時間後）を、第４表に示す。 Measures the solubility of compound (I) acid salt (hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide) in a fed bile acid model solution (hereinafter sometimes referred to as FeSSIF) did.
Each sample of compound (I), hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), and hydrobromide of compound (I) (about 2 mg) was dissolved or suspended in 2 mL of a fed bile acid model solution (FeSSIF) and stirred in a 37 ° C. water bath for 1 hour and 24 hours. This was filtered with DISMIC-13HP (aqueous solvent, pore size 0.20 μm, ADVANTEC), and the filtrate was diluted 10-fold with 30% acetonitrile aqueous solution to obtain a sample solution. For each standard solution (see below), a certain amount was measured by liquid chromatography under the following conditions, and a calibration curve (peak area with respect to sample concentration) was prepared. The above sample solution was also measured in the same manner as the standard solution, the concentration of compound (I) in the sample solution was determined from the peak area of the sample solution using a calibration curve, and the solubility after 1 hour and 24 hours was calculated.
<Standard Solution Preparation Method> 1 mg of each sample was accurately taken, and the total amount was exactly 10 mL with 50% acetonitrile aqueous solution. Further, the obtained solution was diluted at a common ratio of 10, and finally diluted to 1 μg / mL to obtain a standard solution.
<Measurement conditions for liquid chromatography>
Measuring device: LC-20A
Separation column: XBridge C18, 150 mm x 4.6 mm, 5 μm
Column temperature: 40 ° C
Mobile phase: (A) 10 mmol / L ammonium acetate aqueous solution (B) Acetonitrile gradient conditions: (B) 10% / (A) 90% → (B) 70% / (A) 30% ((B) in 30 minutes Concentration increased from 10% to 70%, where% is volume%)
Liquid flow rate: 1.0 mL / min Detection wavelength: 265 nm
Injection volume: 10 μL
Compound retention time: about 19 minutes
The composition of the fed bile acid model solution (FeSSIF) is as follows.
In distilled water 1000mL, sodium taurocholate (Sodium taurocholate) 15mmol / L, lecithin (Lecithin) 3.75mmol / L, sodium hydroxide (NaOH) 4.04g, glacial acetic acid (Glacial Acetic Acid) 8.65g and sodium chloride (NaCl) 11.874 Contains g.
As compound (I), compound (I) ethanol crystallized sample (prepared in Reference Example 3) was used. As the hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), and hydrobromide of compound (I), respectively, Example 1 and 2. Each salt obtained in Reference Examples 4 and 5 was used.
The solubility of the compound (I) ethanol crystallized sample in FeSSIF (after 1 hour and after 24 hours) is shown in Table 4.

Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005

　化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩のFeSSIF への溶解度を第５表に示す。なお、第５表において、Ｎ.Ｔ.は未測定を意味する。 Table 5 shows the solubility of Compound (I) hydrochloride, Compound (I) p-toluenesulfonate, Compound (I) ethanesulfonate, and Compound (I) hydrobromide in FeSSIF. Show. In Table 5, N.T. means not measured.

Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006

　第４表及び第５表から明らかなように、化合物（I）の酸塩（塩酸塩、p-トルエンスルホン酸塩、エタンスルホン酸塩、臭化水素酸塩）は、化合物（I）エタノール結晶化試料よりも摂食胆汁酸モデル液（FeSSIF）に対する溶解度も優れていた。なお、摂食胆汁酸モデル液への溶解性が高いことは、化合物（I）の酸塩の胆汁酸への溶解度が高いことを示唆し、化合物（I）の酸塩の生体内吸収性が高くなることが示唆される。 As is apparent from Tables 4 and 5, the acid salt of the compound (I) (hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide) is obtained from the compound (I) ethanol crystal. Solubility in the fed bile acid model solution (FeSSIF) was also superior to the chlorinated sample. The high solubility in the fed bile acid model solution suggests that the acid salt of the compound (I) is highly soluble in the bile acid, and the in vivo absorbability of the acid salt of the compound (I) is high. Suggested to be higher.

　試験例２：化合物（I）、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩の吸湿性
　化合物（I）、化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩の各試料（約10 mg）を秤量し、温度を25℃に維持したまま相対湿度を変化させて試料重量の増減を測定することにより吸湿性の有無を評価した。
　化合物（I）としては、参考例３で調製した化合物（I）エタノール結晶化試料を用いた。化合物（I）の塩酸塩、化合物（I）のp-トルエンスルホン酸塩、化合物（I）のエタンスルホン酸塩、化合物（I）の臭化水素酸塩としては各々、後記の実施例１及び２、参考例４及び５で得られる各々の塩を用いた。
　吸湿性の測定は以下の条件で行った。
測定条件
温度：25℃
湿度：吸着過程（adsorption）の場合には相対湿度0％から90％まで10％毎に上昇させ、脱着過程（desorption）の場合には相対湿度を90％から0%まで10%毎に降下させた。
最小平衡時間：10分
最大平衡時間：120分
　結果を、図１（化合物（I）エタノール結晶化試料）、図２（化合物（I）の塩酸塩）、図３（化合物（I）のp-トルエンスルホン酸塩）、図４（化合物（I）のエタンスルホン酸塩）、図５（化合物（I）の臭化水素酸塩）に示す。 Test Example 2: Compound (I), hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), hydrobromide of compound (I) Samples of hygroscopic compound (I), hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), hydrobromide of compound (I) (About 10 mg) was weighed, and the presence or absence of hygroscopicity was evaluated by measuring the increase and decrease of the sample weight by changing the relative humidity while maintaining the temperature at 25 ° C.
As the compound (I), the compound (I) ethanol crystallized sample prepared in Reference Example 3 was used. As the hydrochloride of compound (I), p-toluenesulfonate of compound (I), ethanesulfonate of compound (I), and hydrobromide of compound (I), respectively, Example 1 and 2. Each salt obtained in Reference Examples 4 and 5 was used.
The hygroscopic measurement was performed under the following conditions.
Measurement condition temperature: 25 ℃
Humidity: In the case of adsorption process, the relative humidity is increased by 10% from 0% to 90%, and in the case of desorption process, the relative humidity is decreased by 10% from 90% to 0%. It was.
Minimum equilibration time: 10 minutes Maximum equilibrium time: 120 minutes The results are shown in Fig. 1 (compound (I) ethanol crystallized sample), Fig. 2 (hydrochloride of compound (I)), Fig. 3 (compound (I) p- Toluene sulfonate), FIG. 4 (ethane sulfonate of compound (I)) and FIG. 5 (hydrobromide of compound (I)).

　化合物（I）エタノール結晶化試料では各相対湿度における重量変化が大きかった（図１）。
　従って、化合物（Ｉ）エタノール結晶化試料は吸湿性を示すことが明らかになった。
　化合物（I）の塩酸塩及び化合物（I）のp-トルエンスルホン酸塩では各相対湿度における重量変化が小さかった（図２及び図３）。化合物（I）のエタンスルホン酸塩では各相対湿度における重量変化が大きかった（相対湿度20％～60%の環境下において5%という一定の重量増加を示した、図４参照）。化合物（I）の臭化水素酸塩では、高い相対湿度条件においてやや重量増加が認められた（相対湿度70％～の範囲、図５参照）。 The weight change at each relative humidity was large in the compound (I) ethanol crystallized sample (FIG. 1).
Therefore, it became clear that the compound (I) ethanol crystallized sample showed hygroscopicity.
In the hydrochloride of compound (I) and p-toluenesulfonate of compound (I), the change in weight at each relative humidity was small (FIGS. 2 and 3). In the ethanesulfonate salt of Compound (I), the change in weight at each relative humidity was large (showing a constant weight increase of 5% in an environment of 20% to 60% relative humidity, see FIG. 4). In the hydrobromide salt of Compound (I), a slight increase in weight was observed under high relative humidity conditions (range from 70% relative humidity, see FIG. 5).

　従って、化合物（I）の塩酸塩及び化合物（I）のp-トルエンスルホン酸塩は吸湿性を示さないのに対し、化合物（I）のエタンスルホン酸塩及び化合物（I）の臭化水素酸塩は吸湿性を示すことが明らかになった。
　以上より、
　化合物（I）の塩酸塩及び化合物（I）のp-トルエンスルホン酸塩は、化合物（I）（化合物（I）エタノール結晶化試料）に比べて中性溶液での溶解性に優れており、化合物（I）（化合物（I）エタノール結晶化試料）に比べて、吸湿性を示さないという、医薬原末として有利な特徴を有していた。 Therefore, the hydrochloride of Compound (I) and the p-toluenesulfonate of Compound (I) do not exhibit hygroscopicity, whereas the ethanesulfonate of Compound (I) and the hydrobromic acid of Compound (I) The salt was found to be hygroscopic.
From the above,
The hydrochloride of compound (I) and p-toluenesulfonate of compound (I) are superior in solubility in neutral solution compared to compound (I) (compound (I) ethanol crystallized sample), Compared to compound (I) (compound (I) ethanol crystallized sample), it had advantageous characteristics as a pharmaceutical bulk powder that it did not show hygroscopicity.

　更に、化合物（I）のp-トルエンスルホン酸塩は、化合物（I）の塩酸塩に比べて、強酸溶液（JP1）への溶解度がよいことから胃液に対する溶解度がより優れていることが明らかになった。
　化合物（I）の酸塩（塩酸塩、p-トルエンスルホン酸塩、エタンスルホン酸塩、臭化水素酸塩等）は、そのまま単独で投与することも可能であるが、通常各種の医薬組成物として提供するのが望ましい。また、それらの医薬組成物は、ヒトを含む哺乳動物に使用されるものである。 Furthermore, p-toluenesulfonic acid salt of compound (I) has better solubility in gastric juice due to better solubility in strong acid solution (JP1) than hydrochloride of compound (I). became.
Although the acid salt of the compound (I) (hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide, etc.) can be administered alone as it is, various pharmaceutical compositions are usually used. It is desirable to provide as. Moreover, those pharmaceutical compositions are used for mammals including humans.

　本発明の医薬組成物は、活性成分として化合物（I）の酸塩（塩酸塩、p-トルエンスルホン酸塩、エタンスルホン酸塩、臭化水素酸塩等）を単独で、または任意の他の治療のための有効成分との混合物として含有することができる。また、それら医薬組成物は、活性成分を薬学的に許容される一種またはそれ以上の担体（例えば、希釈剤、溶剤、賦形剤等）と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。 The pharmaceutical composition of the present invention comprises an acid salt of the compound (I) (hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide, etc.) alone or as any other active ingredient It can be contained as a mixture with active ingredients for treatment. In addition, these pharmaceutical compositions are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (eg, diluents, solvents, excipients, etc.). It is produced by any known method.

　投与経路としては、治療に際し最も効果的なものを使用するのが望ましく、経口または、例えば静脈内等の非経口をあげることができる。
　投与形態としては、例えば錠剤、注射剤等があげられる。
　経口投与に適当な、例えば錠剤等は、乳糖等の賦形剤、澱粉等の崩壊剤、ステアリン酸マグネシウム等の滑沢剤、ヒドロキシプロピルセルロース等の結合剤等を用いて製造できる。 As the administration route, it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.
Examples of the dosage form include tablets and injections.
For example, tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.

　非経口投与に適当な、例えば注射剤等は、塩溶液、ブドウ糖溶液または塩水とブドウ糖溶液の混合液等の希釈剤または溶剤等を用いて製造できる。
　化合物（I）の酸塩（塩酸塩、p-トルエンスルホン酸塩、エタンスルホン酸塩、臭化水素酸塩等）の投与量及び投与回数は、投与形態、患者の年齢、体重、治療すべき症状の性質もしくは重篤度等により異なるが、通常経口の場合、成人一人あたり、0.01～1000mg、好ましくは0.05～100mgの範囲で、１日１回ないし数回投与する。静脈内投与等の非経口投与の場合、成人一人あたり0.001～1000mg、好ましくは0.01～100mgを１日１回ないし数回投与する。しかしながら、これら投与量及び投与回数に関しては、前述の種々の条件により変動する。 For example, an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution, or a mixed solution of a saline solution and a glucose solution.
The dose and frequency of administration of the salt of Compound (I) (hydrochloride, p-toluenesulfonate, ethanesulfonate, hydrobromide, etc.) should be determined according to the dosage form, patient age, body weight, and treatment Although it varies depending on the nature or severity of symptoms, in the case of oral administration, the dose is usually 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 1000 mg, preferably 0.01 to 100 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.

　以下、本発明を実施例及び参考例によりさらに具体的に説明するが、本発明の範囲はこれらの実施例等に限定されることはない。
参考例１
(E)-N-{2-[2-(1H-インダゾール-3-イル)ビニル]-5-[4-(tert-ブトキシカルボニル)ピペラジン-1-イルメチル]フェニル}-3-メチルチオフェン-2-カルボキサミド・塩酸塩 (化合物5) EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention further more concretely, the scope of the present invention is not limited to these Examples.
Reference example 1
(E) -N- {2- [2- (1H-indazol-3-yl) vinyl] -5- [4- (tert-butoxycarbonyl) piperazin-1-ylmethyl] phenyl} -3-methylthiophene-2 -Carboxamide hydrochloride (Compound 5)

Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007

　上記式中、-Bocは、tert-ブトキシカルボニル基（-COC(CH3)3）を表す。
＜工程１＞
　WO2006／080450の実施例108で得られる(E)-N-{5-ヒドロキシメチル-2-[2-(1H-インダゾール-3-イル)ビニル]フェニル}-3-メチルチオフェン-2-カルボキサミド（化合物4, 1.8g, 4.6 mmol）をN,N-ジメチルホルムアミド（18 mL）に溶解し、塩化メタンスルホニル（0.68 mL, 8.8 mmol）を加えて室温にて4時間攪拌した。反応終了後、テトラヒドロフラン（90 mL）を加えて飽和炭酸水素ナトリウム水溶液（18 mL）と飽和食塩水（18 mL）にて有機層を洗浄した。有機層を減圧濃縮することで粗(E)-N-{5-クロロメチル-2-[2-(1H-インダゾール-3-イル)ビニル]フェニル}-3-メチルチオフェン-2-カルボキサミド(2.6g)を得た。
＜工程２＞
　工程１で得られた粗(E)-N-{5-クロロメチル-2-[2-(1H-インダゾール-3-イル)ビニル]フェニル}-3-メチルチオフェン-2-カルボキサミド（2.6 g）にN,N-ジメチルアセトアミド（18 mL）、N,N-ジイソプロピルエチルアミン（0.79 mL, 4.4 mmol）、及び1-(tert-ブトキシカルボニル)ピぺラジン（1.2 g, 6.6 mmol）を加えて80℃で2時間加熱還流した。反応終了後、室温まで冷却し、水(90 mL)を加えてから、酢酸エチル抽出（36 mL）を2回行った。有機層を飽和食塩水(10 mL)にて洗浄した後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣にエタノール(72 mL)を加えて4℃に冷却後、濃塩酸(1.5 mL)を添加して2.5時間攪拌した。濾過して得られる固体を乾燥し、標記化合物5（2.1 ｇ, 77%）を得た。
1H-NMR (DMSO-d6) δ 1.42 (s, 9H), 2.50 (s, 3H), 2.94-3.47 (m, 6H), 4.06 (m, 2H), 4.38 (brs, 2H), 7.07-7.14 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H) , 7.50-7.70 (m, 6H), 8.03-8.08 (m, 2H), 10.0 (br, 1H), 13.2 (br, 1H).
ESI-MS (m/z); 558 [M+H]+
参考例２
(E)-N-{2-[2-(1H-インダゾール-3-イル)ビニル]-5-（ピペラジン-1-イルメチル）フェニル}-3-メチルチオフェン-2-カルボキサミド（化合物6） In the above formula, -Boc represents a tert-butoxycarbonyl group (-COC (CH 3 ) 3 ).
<Step 1>
(E) -N- {5-hydroxymethyl-2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide obtained in Example 108 of WO2006 / 080450 ( Compound 4, 1.8 g, 4.6 mmol) was dissolved in N, N-dimethylformamide (18 mL), methanesulfonyl chloride (0.68 mL, 8.8 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, tetrahydrofuran (90 mL) was added, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (18 mL) and saturated brine (18 mL). The organic layer was concentrated under reduced pressure to give crude (E) -N- {5-chloromethyl-2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide (2.6 g) was obtained.
<Process 2>
Crude (E) -N- {5-chloromethyl-2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide (2.6 g) obtained in step 1 N, N-dimethylacetamide (18 mL), N, N-diisopropylethylamine (0.79 mL, 4.4 mmol), and 1- (tert-butoxycarbonyl) piperazine (1.2 g, 6.6 mmol) were added to 80 ° C. And heated at reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (90 mL) was added, and ethyl acetate extraction (36 mL) was performed twice. The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethanol (72 mL) was added to the obtained residue and the mixture was cooled to 4 ° C., concentrated hydrochloric acid (1.5 mL) was added, and the mixture was stirred for 2.5 hr. The solid obtained by filtration was dried to obtain the title compound 5 (2.1 g, 77%).
1 H-NMR (DMSO-d 6 ) δ 1.42 (s, 9H), 2.50 (s, 3H), 2.94-3.47 (m, 6H), 4.06 (m, 2H), 4.38 (brs, 2H), 7.07- 7.14 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.50-7.70 (m, 6H), 8.03-8.08 (m, 2H), 10.0 (br, 1H), 13.2 (br, 1H) .
ESI-MS (m / z); 558 [M + H] +
Reference example 2
(E) -N- {2- [2- (1H-indazol-3-yl) vinyl] -5- (piperazin-1-ylmethyl) phenyl} -3-methylthiophene-2-carboxamide (Compound 6)

Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008

　上記式中、-Bocは、tert-ブトキシカルボニル基（‐COC(CH3)3）を表す。
　参考例１で得られる化合物5（4.0 ｇ, 6.7 mmol）をメタノール（0.16 L）、水（32 ｍL）、及び濃塩酸（8 mL）の混合液に加えて70℃で1.5時間攪拌した。反応溶液を4℃まで冷却し、4 mol/L水酸化ナトリウム水溶液(26 mL)をゆっくりと加えてpH11とした後に、減圧下にてメタノールを留去し、エタノール（40 mL）を加えて、水 (40 mL)を滴下した。濾過して得られる固体を減圧乾燥し、標記化合物6（3.1 g, 定量的）を得た。
1H-NMR (DMSO-d6) δ 2.32 (br, 4H), 2.50 (s, 3H), 2.68-2.72 (m, 4H), 3.45 (s, 2H), 7.05-7.09 (m, 2H), 7.24-7.39 (m, 3H), 7.47 (d, J = 16.6 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 16.6 Hz, 1H), 7.69 (d, J = 5.0 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 9.85 (br, 1H), 13.2 (br, 1H).
参考例３
(E)-N-{5-[4-(2-ヒドロキシアセチル)ピペラジン-1-イルメチル]-2-[2-(1H-インダゾール-3-イル)ビニル]フェニル}-3-メチルチオフェン-2-カルボキサミド（化合物（I））の合成（化合物（I）エタノール結晶化試料） In the above formula, -Boc represents a tert-butoxycarbonyl group (-COC (CH 3 ) 3 ).
Compound 5 (4.0 g, 6.7 mmol) obtained in Reference Example 1 was added to a mixture of methanol (0.16 L), water (32 mL), and concentrated hydrochloric acid (8 mL), and the mixture was stirred at 70 ° C. for 1.5 hours. The reaction solution was cooled to 4 ° C, 4 mol / L aqueous sodium hydroxide solution (26 mL) was slowly added to adjust to pH 11, methanol was distilled off under reduced pressure, ethanol (40 mL) was added, Water (40 mL) was added dropwise. The solid obtained by filtration was dried under reduced pressure to obtain the title compound 6 (3.1 g, quantitative).
1 H-NMR (DMSO-d 6 ) δ 2.32 (br, 4H), 2.50 (s, 3H), 2.68-2.72 (m, 4H), 3.45 (s, 2H), 7.05-7.09 (m, 2H), 7.24-7.39 (m, 3H), 7.47 (d, J = 16.6 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 16.6 Hz, 1H), 7.69 (d, J = 5.0 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 9.85 (br, 1H), 13.2 (br, 1H).
Reference example 3
(E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 -Synthesis of carboxamide (compound (I)) (compound (I) ethanol crystallization sample)

Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009

　参考例２で得られる(E)-N-{2-[2-(1H-インダゾール-3-イル)ビニル]-5-（ピペラジン-1-イルメチル）フェニル}-3-メチルチオフェン-2-カルボキサミド(化合物6、500mg, 1.09mmol）のN,N-ジメチルアセトアミド（10mL）溶液に塩化アセトキシアセチル（0.141mL、1.31mmol, 1.1 当量）を加えて30分間攪拌した。水（60mL）と飽和炭酸水素ナトリウム水溶液（80mL）を加え、酢酸エチル（100mL）で抽出し、有機層を飽和食塩水(100mL)で洗浄後、無水硫酸ナトリウムで乾燥した。
　減圧濃縮して得られる残渣（化合物（I）粗成物）にメタノール（5.0mL）、水（1.0mL）、及び炭酸カリウム(75 mg, 0.501mmol)を加えて1時間攪拌した。水(5ｍｌ)を加えてからエタノール(1.0 mL)を加え、更に水（10mL）を滴下した。混合液を40℃に加熱後、4℃まで冷却して1時間攪拌後に濾過することにより白色固体として、化合物（I）［化合物（I）エタノール結晶化試料］（535mg, 95％）を得た。
1H-NMR (DMSO-d6)　δ 2.40 (br, 4H), 2.51 (s, 3H), 3.49 (br, 4H), 3.54 (s, 2H), 4.07 (d, J = 5.1 Hz, 2H), 4.54 (t, J = 5.1 Hz, 1H), 7.05-7.11 (m, 2H), 7.27-7.39 (m, 3H), 7.48 (d, J = 16.7 Hz, 1H), 7.51-7.58 (m, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.70 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 9.87 (br, 1H), 13.1 (br, 1H). (E) -N- {2- [2- (1H-indazol-3-yl) vinyl] -5- (piperazin-1-ylmethyl) phenyl} -3-methylthiophene-2-carboxamide obtained in Reference Example 2 To a solution of (Compound 6, 500 mg, 1.09 mmol) in N, N-dimethylacetamide (10 mL) was added acetoxyacetyl chloride (0.141 mL, 1.31 mmol, 1.1 eq) and stirred for 30 minutes. Water (60 mL) and saturated aqueous sodium hydrogen carbonate solution (80 mL) were added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate.
Methanol (5.0 mL), water (1.0 mL), and potassium carbonate (75 mg, 0.501 mmol) were added to the residue (compound (I) crude product) obtained by concentration under reduced pressure, and the mixture was stirred for 1 hour. Water (5 ml) was added, ethanol (1.0 mL) was added, and water (10 mL) was further added dropwise. The mixture was heated to 40 ° C., cooled to 4 ° C., stirred for 1 hour and filtered to obtain Compound (I) [Compound (I) ethanol crystallized sample] (535 mg, 95%) as a white solid. .
1 H-NMR (DMSO-d 6 ) δ 2.40 (br, 4H), 2.51 (s, 3H), 3.49 (br, 4H), 3.54 (s, 2H), 4.07 (d, J = 5.1 Hz, 2H) , 4.54 (t, J = 5.1 Hz, 1H), 7.05-7.11 (m, 2H), 7.27-7.39 (m, 3H), 7.48 (d, J = 16.7 Hz, 1H), 7.51-7.58 (m, 1H ), 7.61 (d, J = 16.7 Hz, 1H), 7.70 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 9.87 (br, 1H), 13.1 (br, 1H).

(E)-N-{5-[4-(2-ヒドロキシアセチル)ピペラジン-1-イルメチル]-2-[2-(1H-インダゾール-3-イル)ビニル]フェニル}-3-メチルチオフェン-2-カルボキサミド・塩酸塩（化合物（I）の塩酸塩）
　参考例３で得られた化合物（I）（100 mg, 0.194 mmol）にエタノール3 mLを加えて65℃に加熱し、得られた懸濁液に塩酸1.0 mol/L エタノール溶液を430 μL（0.427 mmol）加えた。得られた溶液を室温に冷却し、一晩撹拌後さらに冷蔵庫にて2時間以上撹拌を継続した。濾取により得られた結晶を、減圧下50℃にて乾燥し、化合物（I）の塩酸塩（92mg, 収率85.9％）を得た。
1H NMR (DMSO-d6)　δ (ppm): 2.50 (s, 3H), 2.80-4.50 (12H), 7.06 (d, J= 5.0 Hz, 1H), 7.10 (m, 1H), 7.37 (m, 1H), 7.53-7.68 (m, 5H), 7.71 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 6.3 Hz, 1H), 8.05 (d, J = 6.1 Hz, 1H), 10.02 (s, 1H), 11.17 (brs, 1H), 13.24 (brs, 1H).
元素分析：　計算値C28H30ClN5O3Sとして： C, 60.91; H 5.48; N 12.69. 実測値： C, 60.64; H, 5.42; N, 12.44. (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 -Carboxamide hydrochloride (hydrochloride of compound (I))
3 mL of ethanol was added to compound (I) (100 mg, 0.194 mmol) obtained in Reference Example 3 and heated to 65 ° C., and 1.0 mol / L hydrochloric acid ethanol solution was added to 430 μL (0.427) of the resulting suspension. mmol). The resulting solution was cooled to room temperature, stirred overnight, and further stirred in a refrigerator for 2 hours or more. The crystals obtained by filtration were dried at 50 ° C. under reduced pressure to obtain hydrochloride (92 mg, yield 85.9%) of compound (I).
1 H NMR (DMSO-d 6 ) δ (ppm): 2.50 (s, 3H), 2.80-4.50 (12H), 7.06 (d, J = 5.0 Hz, 1H), 7.10 (m, 1H), 7.37 (m , 1H), 7.53-7.68 (m, 5H), 7.71 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 6.3 Hz, 1H), 8.05 (d, J = 6.1 Hz, 1H), 10.02 (s, 1H), 11.17 (brs, 1H), 13.24 (brs, 1H).
Elemental analysis: Calculated as C 28 H 30 ClN 5 O 3 S: C, 60.91; H 5.48; N 12.69. Found: C, 60.64; H, 5.42; N, 12.44.

(E)-N-{5-[4-(2-ヒドロキシアセチル)ピペラジン-1-イルメチル]-2-[2-(1H-インダゾール-3-イル)ビニル]フェニル}-3-メチルチオフェン-2-カルボキサミド・p-トルエンスルホン酸塩（化合物（I）のp-トルエンスルホン酸塩）
　参考例３で得られた化合物（I）（100 mg, 0.194 mmol）にエタノール3 mLを加えて65℃に加熱し、得られた懸濁液にp-トルエンスルホン酸1.0 mol/L エタノール溶液を430 μL（0.427 mmol）加えた。得られた溶液を室温に冷却し、一晩撹拌後さらに冷蔵庫にて2時間以上撹拌を継続した。濾取により得られた結晶を、減圧下50℃にて乾燥し、化合物（I）のp-トルエンスルホン酸塩（104 mg, 収率77.9％）を得た。
1H NMR (DMSO-d6)　δ (ppm): 2.21 (s, 3H), 2.44 (s, 3H), 2.80-4.50 (12H), 6.95-7.10 (m, 4H), 7.29-7.63 (m, 8H), 7.66 (d, J = 5.0 Hz, 1H), 7.95-8.05 (m, 2H), 9.80 (brs, 1H), 9.95 (s, 1H), 13.17 (brs, 1H); 
元素分析：　計算値C35H37N5O6S2として： C, 61.12; H 5.42; N 10.18. 実測値： C, 60.91; H, 5.30; N, 10.16.
参考例４
(E)-N-{5-[4-(2-ヒドロキシアセチル)ピペラジン-1-イルメチル]-2-[2-(1H-インダゾール-3-イル)ビニル]フェニル}-3-メチルチオフェン-2-カルボキサミド・エタンスルホン酸塩（化合物（I）のエタンスルホン酸塩）
　参考例３で得られた化合物（I）（100 mg, 0.194 mmol）にエタノール3 mLを加えて65℃に加熱し、得られた懸濁液にエタンスルホン酸1.0 mol/L エタノール溶液を430 μL（0.427 mmol）加えた。得られた溶液を室温に冷却し、一晩撹拌後さらに冷蔵庫にて2時間以上撹拌を継続した。濾取により得られた結晶を、減圧下50℃にて乾燥し、化合物（I）のエタンスルホン酸塩（81 mg, 収率66.7％）を得た。
1H NMR (DMSO-d6)　δ (ppm): 1.06 (t, J = 7.3 Hz, 3H), 2.39 (q, J = 7.3 Hz, 2H), 2.50 (s, 3H), 2.80-4.50 (12H), 7.07 (d, J = 5.0 Hz, 1H), 7.11 (m, 1H), 7.37 (m, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.54-7.69 (m, 4H), 7.72 (d, J = 5.0 Hz, 1H), 8.00-8.10 (m, 2H), 9.94 (brs, 1H), 10.01 (s, 1H), 13.23 (brs, 1H); 
元素分析：　計算値　C30H35N5O6S2 2.4H2Oとして: C, 53.86; H 6.00; N 10.47. 実測値：　C, 53.87; H, 5.82; N, 10.39.
参考例５
(E)-N-{5-[4-(2-ヒドロキシアセチル)ピペラジン-1-イルメチル]-2-[2-(1H-インダゾール-3-イル)ビニル]フェニル}-3-メチルチオフェン-2-カルボキサミド・臭化水素酸塩（化合物（I）の臭化水素酸塩）
　参考例３で得られた化合物（I）（150 mg, 0.291 mmol）にエタノール5 mLを加えて70℃に加熱し、得られた懸濁液に臭化水素酸1.0 mol/L エタノール溶液を640 μL（0.640 mmol）加えた。得られた溶液を室温に冷却し、一晩撹拌後さらに冷蔵庫にて2時間以上撹拌を継続した。濾取により得られた結晶を、減圧下50℃にて乾燥し、化合物（I）の臭化水素酸塩（151 mg, 収率87.0％）を得た。
1H NMR (DMSO-d6)　δ (ppm): 2.50 (s, 3H),　2.80-4.50 (12H), 7.07 (d, J = 5.0 Hz, 1H), 7.11 (m, 1H), 7.37 (m, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.54-7.69 (m, 4H), 7.72 (d, J = 5.0 Hz, 1H), 8.00-8.10 (m, 2H), 10.02 (s, 2H), 13.23 (brs, 1H).
元素分析：　計算値　C28H30BrN5O3Sとして： C, 56.38; H 5.07; N 11.74. 実測値：　C, 56.27; H, 4.96; N, 11.55. (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 -Carboxamide / p-toluenesulfonate (p-toluenesulfonate of compound (I))
3 mL of ethanol was added to the compound (I) (100 mg, 0.194 mmol) obtained in Reference Example 3 and heated to 65 ° C., and 1.0 mol / L ethanol solution of p-toluenesulfonic acid was added to the resulting suspension. 430 μL (0.427 mmol) was added. The resulting solution was cooled to room temperature, stirred overnight, and further stirred in a refrigerator for 2 hours or more. The crystals obtained by filtration were dried at 50 ° C. under reduced pressure to obtain p-toluenesulfonate (104 mg, yield 77.9%) of compound (I).
1 H NMR (DMSO-d 6 ) δ (ppm): 2.21 (s, 3H), 2.44 (s, 3H), 2.80-4.50 (12H), 6.95-7.10 (m, 4H), 7.29-7.63 (m, 8H), 7.66 (d, J = 5.0 Hz, 1H), 7.95-8.05 (m, 2H), 9.80 (brs, 1H), 9.95 (s, 1H), 13.17 (brs, 1H);
Elemental analysis: Calculated C 35 H 37 N 5 O 6 S 2:. C, 61.12; H 5.42; N 10.18 Found: C, 60.91; H, 5.30 ; N, 10.16.
Reference example 4
(E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 -Carboxamide ethanesulfonate (ethanesulfonate of compound (I))
3 mL of ethanol was added to the compound (I) (100 mg, 0.194 mmol) obtained in Reference Example 3 and heated to 65 ° C., and 430 μL of ethanesulfonic acid 1.0 mol / L ethanol solution was added to the resulting suspension. (0.427 mmol) was added. The resulting solution was cooled to room temperature, stirred overnight, and further stirred in a refrigerator for 2 hours or more. The crystals obtained by filtration were dried at 50 ° C. under reduced pressure to obtain the ethanesulfonate salt of compound (I) (81 mg, yield 66.7%).
1 H NMR (DMSO-d 6 ) δ (ppm): 1.06 (t, J = 7.3 Hz, 3H), 2.39 (q, J = 7.3 Hz, 2H), 2.50 (s, 3H), 2.80-4.50 (12H ), 7.07 (d, J = 5.0 Hz, 1H), 7.11 (m, 1H), 7.37 (m, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.54-7.69 (m, 4H), 7.72 (d, J = 5.0 Hz, 1H), 8.00-8.10 (m, 2H), 9.94 (brs, 1H), 10.01 (s, 1H), 13.23 (brs, 1H);
Elemental analysis: Calculated C 30 H 35 N 5 O 6 S 2 2.4 As H 2 O: C, 53.86; H 6.00; N 10.47. Found: C, 53.87; H, 5.82; N, 10.39.
Reference Example 5
(E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 -Carboxamide hydrobromide (hydrobromide of compound (I))
Ethanol (5 mL) was added to the compound (I) (150 mg, 0.291 mmol) obtained in Reference Example 3 and heated to 70 ° C., and a 1.0 mol / L ethanol solution of hydrobromic acid was added to the resulting suspension. μL (0.640 mmol) was added. The resulting solution was cooled to room temperature, stirred overnight, and further stirred in a refrigerator for 2 hours or more. The crystals obtained by filtration were dried at 50 ° C. under reduced pressure to obtain the hydrobromide salt of compound (I) (151 mg, yield 87.0%).
1 H NMR (DMSO-d 6 ) δ (ppm): 2.50 (s, 3H), 2.80-4.50 (12H), 7.07 (d, J = 5.0 Hz, 1H), 7.11 (m, 1H), 7.37 (m , 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.54-7.69 (m, 4H), 7.72 (d, J = 5.0 Hz, 1H), 8.00-8.10 (m, 2H), 10.02 (s, 2H), 13.23 (brs, 1H).
Elemental analysis: Calculated as C 28 H 30 BrN 5 O 3 S: C, 56.38; H 5.07; N 11.74. Found: C, 56.27; H, 4.96; N, 11.55.

製剤例（錠剤)
　常法により、次の組成からなる錠剤を調製する。化合物（I）の塩酸塩40g、乳糖286.8g及び馬鈴薯澱粉60gを混合し、これにヒドロキシプロピルセルロースの10%水溶液120gを加える。得られた混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム1.2gを加えて混合し、径8mmの杵をもった打錠機(菊水社製RT-15型)で打錠を行って、錠剤(1錠あたり活性成分20mgを含有する)を得る。
処方
　　　　化合物（I）の塩酸塩　　　　　　　  20　　mg
　　　　乳糖　　　　　　　　　　　　　　  143.4　mg
　　　　馬鈴薯澱粉　　　　　　　　　　　　 30　　mg
　　　　ヒドロキシプロピルセルロース　　　　6　　mg
　　　　ステアリン酸マグネシウム　　　　　　0.6　mg 　
　　　　　　　　　　　　　　　　　　　　　200　　mg Formulation example (tablet)
A tablet having the following composition is prepared by a conventional method. Compound (I) hydrochloride (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, and 10% aqueous solution of hydroxypropylcellulose (120 g) is added thereto. The obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this was added 1.2 g of magnesium stearate, mixed, and tableted with a tableting machine (RT-15 type manufactured by Kikusui Co., Ltd.) with a 8 mm diameter punch, and tablets (containing 20 mg of active ingredient per tablet) )
Formulation Hydrochloride of Compound (I) 20 mg
Lactose 143.4 mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
200 mg

製剤例（錠剤）
　実施例３に準じて次の組成からなる錠剤を得る。
処方
　　　　化合物（I）のp-トルエンスルホン酸塩　　　　　20　　mg
　　　　乳糖　　　　　　　　　　　　　　　　　　　　 143.4　mg
　　　　馬鈴薯澱粉　　　　　　　　　　　　　　　　　　30　　mg
　　　　ヒドロキシプロピルセルロース　　　　　　　　　 6　　mg
　　　　ステアリン酸マグネシウム　　　　　　　　　　　 0.6　mg 
　　　　　　　　　　 　　　　　　　　　　　　　　　　200　　mg Formulation example (tablet)
A tablet having the following composition is obtained according to Example 3.
Formulation Compound (I) p-toluenesulfonate 20 mg
Lactose 143.4 mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
200 mg

　本発明により、癌等の異常な細胞増殖の治療に有用な、（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの酸塩が提供される。 According to the present invention, (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-) is useful for the treatment of abnormal cell proliferation such as cancer. Indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide acid salt is provided.

Claims (4)

（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドのp-トルエンスルホン酸塩及び（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの塩酸塩から選ばれる、一つの（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの酸塩。 (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 -Carboxamide p-toluenesulfonate and (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl ] (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2] selected from the hydrochloride salt of] phenyl} -3-methylthiophene-2-carboxamide -(1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide acid salt. （E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドのp-トルエンスルホン酸塩。 (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 Carboxamide p-toluenesulfonate. （E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの塩酸塩。 (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2 -Carboxamide hydrochloride. 癌の治療に有効な量の、（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドのp-トルエンスルホン酸塩及び（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの塩酸塩から選ばれる少なくとも一つの（E）‐N‐｛5‐[4‐（2‐ヒドロキシアセチル）ピペラジン‐1‐イルメチル]‐2‐[2‐(1H‐インダゾール‐3‐イル)ビニル]フェニル｝‐3‐メチルチオフェン‐２‐カルボキサミドの酸塩、並びに薬学的に許容される担体を含有する医薬組成物。
  An effective amount of (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] for the treatment of cancer P-Toluenesulfonate of phenyl} -3-methylthiophene-2-carboxamide and (E) -N- {5- [4- (2-hydroxyacetyl) piperazin-1-ylmethyl] -2- [2- ( 1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide hydrochloride selected from at least one (E) -N- {5- [4- (2-hydroxyacetyl) piperazine- 1-ylmethyl] -2- [2- (1H-indazol-3-yl) vinyl] phenyl} -3-methylthiophene-2-carboxamide acid salt and pharmaceutical composition containing a pharmaceutically acceptable carrier .
PCT/JP2011/063901 2010-06-17 2011-06-17 Useful salts of indazole derivative Ceased WO2011158931A1 (en)

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WO2012115226A1 (en) * 2011-02-24 2012-08-30 協和発酵キリン株式会社 Therapeutic agent for cancer
WO2025014774A1 (en) 2023-07-07 2025-01-16 Viridian Therapeutics, Inc. Methods of treating active and chronic thyroid eye disease

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JPS62135491A (en) * 1985-12-06 1987-06-18 Ajinomoto Co Inc Aromatic sulfonate salt of proline derivative
JPH083170A (en) * 1994-06-14 1996-01-09 Biochem Gmbh Purification of cephalosporin salt
JPH10101674A (en) * 1996-08-06 1998-04-21 Taisho Pharmaceut Co Ltd Paratoluenesulfonate hydrate of thiazoline compound
JP2002220336A (en) * 2000-11-22 2002-08-09 Sankyo Co Ltd Preventive and therapeutic agents for diabetes containing condensed heterocyclic compound
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WO2006080450A1 (en) * 2005-01-27 2006-08-03 Kyowa Hakko Kogyo Co., Ltd. Igf-1r inhibitor

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012115226A1 (en) * 2011-02-24 2012-08-30 協和発酵キリン株式会社 Therapeutic agent for cancer
WO2025014774A1 (en) 2023-07-07 2025-01-16 Viridian Therapeutics, Inc. Methods of treating active and chronic thyroid eye disease

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