JP2010254615A - Crystal of diamine derivative - Google Patents

Crystal of diamine derivative Download PDF

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JP2010254615A
JP2010254615A JP2009106176A JP2009106176A JP2010254615A JP 2010254615 A JP2010254615 A JP 2010254615A JP 2009106176 A JP2009106176 A JP 2009106176A JP 2009106176 A JP2009106176 A JP 2009106176A JP 2010254615 A JP2010254615 A JP 2010254615A
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crystal
compound
crystal according
carbonyl
embolism
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Makoto Ono
小野  誠
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a crystal of compound (I) which has an inhibitory action on activated blood coagulation factor X and is useful as a pharmaceutical compound for preventing and/treating thrombic and/or embolic diseases. <P>SOLUTION: The crystal of N<SP>1</SP>-(5-chloropyridin-2-yl)-N<SP>2</SP>-((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-ä[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate-monohydrate is represented by formula (I). <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

本発明は、活性化血液凝固第X因子(FXa)の阻害作用を示し、血栓性疾患の予防剤および/または治療剤として有用な化合物の結晶に関する。   The present invention relates to a crystal of a compound that exhibits an inhibitory action on activated blood coagulation factor X (FXa) and is useful as a prophylactic and / or therapeutic agent for thrombotic diseases.

活性化血液凝固第X因子(FXa)の阻害作用を示し、血栓性疾患の予防および/または治療薬として有用な化合物として、下記の一般式(I)   As a compound that exhibits an inhibitory action on activated blood coagulation factor X (FXa) and is useful as a preventive and / or therapeutic agent for thrombotic diseases, the following general formula (I)

で表されるN−(5−クロロピリジン−2−イル)−N−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド p−トルエンスルホン酸塩 1水和物(以下、化合物Iと称する場合がある。)が知られている(特許文献1〜特許文献5)。 N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide p-toluenesulfonate monohydrate (hereinafter sometimes referred to as Compound I) Is known (Patent Documents 1 to 5).

これまでに、医薬化合物として有用である化合物(I)の結晶に関する詳細な報告はない。   So far, there is no detailed report on crystals of compound (I) that are useful as pharmaceutical compounds.

国際公開第03/000657号パンフレットInternational Publication No. 03/000657 Pamphlet 国際公開第03/000680号パンフレットWO03 / 000680 pamphlet 国際公開第03/016302号パンフレットWO03 / 016302 Pamphlet 国際公開第04/058715号パンフレットInternational Publication No. 04/058715 pamphlet 国際公開第07/032498号パンフレットInternational Publication No. 07/032498 Pamphlet

本発明の課題は、血栓性および/または塞栓性疾患の予防および/または治療用の医薬化合物として有用である化合物Iの結晶を提供することにある。   An object of the present invention is to provide crystals of Compound I that are useful as pharmaceutical compounds for the prevention and / or treatment of thrombotic and / or embolic diseases.

本発明は
[1]下記の式(I)
The present invention provides [1] the following formula (I)

で表される、N−(5−クロロピリジン−2−イル)−N−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド p−トルエンスルホン酸塩 1水和物の結晶;
[2]粉末X線回折による回折角(2θ)として、5.38、8.08、10.8、13.5、15.0、16.9、17.6、20.5、21.1、22.7、23.5、26.0、27.3、27.6および30.0(°)に特徴的ピークを有する[1]に記載の結晶;
[3]さらに、下記の(a)〜(c):
(a)約250℃〜約270℃に2本の吸熱ピークを有する熱分析(DTA)プロフィール;
(b)1675、1614、1503、1222、1171、1033および1012cm−1付近に特徴的な吸収帯を有する赤外吸収スペクトルパターン;および
(c)融点(分解)が約246℃〜約250℃;
からなる群より選ばれる1つ以上の特徴を有する、[2]に記載の結晶;
[4][1]〜[3]のいずれか1に記載の結晶を含有する医薬;
[5][1]〜[3]のいずれか1に記載の結晶を含有する活性化血液凝固第X因子(FXa)阻害剤;
[6][1]〜[3]のいずれか1に記載の結晶を含有する血液凝固抑制剤;
[7][1]〜[3]のいずれか1に記載の結晶を含有する血栓または塞栓の予防および/または治療剤;
[8][1]〜[3]のいずれか1に記載の結晶を含有する脳梗塞、脳塞栓、肺梗塞、肺塞栓、心筋梗塞、狭心症、非弁膜性心房細動(NVAF)に伴う血栓および/または塞栓症、深部静脈血栓症、外科的手術後の深部静脈血栓症、人工弁/関節置換後の血栓形成、股関節全置換術(THR)後の血栓塞栓症、膝関節全置換術(TKR)後の血栓塞栓症、股関節骨折手術(HFS)後の血栓塞栓症、血行再建後の血栓形成および/または再閉塞、バージャー病、汎発性血管内凝固症候群、全身性炎症性反応症候群(SIRS)、多臓器不全(MODS)、体外循環時の血栓形成あるいは採血時の血液凝固の予防剤および/または治療剤;
[9][1]〜[3]のいずれか1に記載の結晶および薬理上許容される担体を含有する医薬組成物、
に関する。
N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide p-toluenesulfonate monohydrate crystals;
[2] 5.38, 8.08, 10.8, 13.5, 15.0, 16.9, 17.6, 20.5, 21.1 as diffraction angles (2θ) by powder X-ray diffraction , 22.7, 23.5, 26.0, 27.3, 27.6 and 30.0 (°) having a characteristic peak [1];
[3] Further, the following (a) to (c):
(A) a thermal analysis (DTA) profile having two endothermic peaks at about 250 ° C. to about 270 ° C .;
(B) an infrared absorption spectral pattern having characteristic absorption bands around 1675, 1614, 1503, 1222, 1171, 1033 and 1012 cm −1 ; and (c) a melting point (decomposition) of about 246 ° C. to about 250 ° C .;
The crystal according to [2], having one or more characteristics selected from the group consisting of:
[4] A medicine containing the crystal according to any one of [1] to [3];
[5] An activated blood coagulation factor X (FXa) inhibitor containing the crystal according to any one of [1] to [3];
[6] A blood coagulation inhibitor containing the crystal according to any one of [1] to [3];
[7] A prophylactic and / or therapeutic agent for a thrombus or embolus containing the crystal according to any one of [1] to [3];
[8] For cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, non-valvular atrial fibrillation (NVAF) containing the crystal according to any one of [1] to [3] Thrombosis and / or embolism, deep vein thrombosis, deep vein thrombosis after surgery, thrombus formation after prosthetic valve / joint replacement, thromboembolism after total hip replacement (THR), total knee replacement Thromboembolism after surgery (TKR), thromboembolism after hip fracture surgery (HFS), thrombus formation and / or reocclusion after revascularization, Buerger's disease, generalized intravascular coagulation syndrome, systemic inflammatory response Preventive and / or therapeutic agent for syndrome (SIRS), multiple organ failure (MODS), thrombus formation during extracorporeal circulation or blood coagulation during blood collection;
[9] A pharmaceutical composition comprising the crystal according to any one of [1] to [3] and a pharmacologically acceptable carrier,
About.

本発明によれば、血栓性および/または塞栓性疾患の予防および/または治療用の医薬化合物として有用である化合物Iの結晶が提供される。   According to the present invention, there are provided crystals of Compound I that are useful as pharmaceutical compounds for the prevention and / or treatment of thrombotic and / or embolic diseases.

化合物Iの結晶の粉末X線回折パターンを示す。縦軸に強度(cps)を横軸に回折角(2θ(°))を示す。1 shows a powder X-ray diffraction pattern of Compound I crystals. The vertical axis represents intensity (cps), and the horizontal axis represents diffraction angle (2θ (°)). 化合物Iの結晶の粉末X線回折の特徴的ピークおよびその相対強度を示す。The characteristic peak of powder X-ray diffraction of the compound I crystal and its relative intensity are shown. 化合物Iの結晶の熱分析(TG/DTA)パターンを示す。縦軸に重量変化(%)と熱量(μV)、横軸に温度(℃)を示す。2 shows a thermal analysis (TG / DTA) pattern of crystals of Compound I. The vertical axis shows weight change (%) and heat (μV), and the horizontal axis shows temperature (° C.). 化合物Iの結晶の赤外吸収スペクトルパターンを示す。縦軸に透過率(%)と横軸に波数(cm−1)を示す。2 shows an infrared absorption spectrum pattern of a crystal of Compound I. The vertical axis represents transmittance (%) and the horizontal axis represents wave number (cm −1 ). 化合物Iの結晶の赤外吸収スペクトルの特徴的な吸収帯およびその強度を示す。The characteristic absorption band of the infrared absorption spectrum of the crystal of Compound I and its intensity are shown. 化合物Iの結晶の吸脱湿挙動を示す。2 shows the moisture absorption / desorption behavior of Compound I crystals.

以下に、本発明を詳細に説明する。
下記の式(II)
The present invention is described in detail below.
Formula (II) below

で表される、N−(5−クロロピリジン−2−イル)−N−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド(N1-(5-chloropyridin-2-yl)-N2-((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4, 5, 6, 7-tetrahydrothiazolo[5, 4-c] pyridin-2-yl)carbonyl]amino}cyclohexyl) ethanediamide)(以下、化合物IIと称する場合がある。)は、化合物Iのフリー体であり、国際一般名称(International Nonproprietary Names、INN)を、エドキサバン(edoxaban)、N-(5-クロロピリジン-2-イル)-N'-[(1S, 2R, 4S)-4-(N, N-ジメチルカルバモイル)-2-(5-メチル-4, 5, 6, 7-テトラヒドロ [1, 3]チアゾロ [5, 4-c]ピリジン-2-カルボキサミド)シクロヘキシル]オキサミド(N-(5-chloropyridin-2-yl)-N'-[(1S, 2R, 4S)-4-(N, N-dimethylcarbamoyl)-2-(5-methyl-4, 5, 6, 7-tetrahydro[1, 3]thiazolo[5, 4-c]pyridine-2-carboxamido)cyclohexyl]oxamide)という。 N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide (N 1- (5-chloropyridin-2-yl) -N 2 -(( 1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] amino } cyclohexyl) ethanediamide) (hereinafter sometimes referred to as Compound II) is a free form of Compound I, International Nonproprietary Names (INN), Edoxaban, N- (5-chloro Pyridin-2-yl) -N '-[(1S, 2R, 4S) -4- (N, N-dimethylcarbamoyl) -2- (5-methyl-4, 5, 6, 7-tetrahydro [1, 3 ] Thiazolo [5, 4-c] pyridine-2-carboxamide) Chlohexyl] oxamide (N- (5-chloropyridin-2-yl) -N '-[(1S, 2R, 4S) -4- (N, N-dimethylcarbamoyl) -2- (5-methyl-4, 5, 6 , 7-tetrahydro [1,3] thiazolo [5,4-c] pyridine-2-carboxamido) cyclohexyl] oxamide).

化合物IIを製造する方法は特に限定されないが、例えば、特許文献1〜5に記載の方法またはこれらに準ずる方法で製造することができる。   Although the method of manufacturing compound II is not specifically limited, For example, it can manufacture by the method of patent documents 1-5, or the method according to these.

化合物Iの結晶は、例えば、化合物IIにp−トルエンスルホン酸のエタノール溶液を添加後、含水エタノールを追加で添加して化合物IIを溶解し、その後反応液を冷却して結晶を析出させることによって得ることができる。   The crystal of compound I can be obtained, for example, by adding ethanol solution of p-toluenesulfonic acid to compound II, then adding water-containing ethanol to dissolve compound II, and then cooling the reaction solution to precipitate crystals. Obtainable.

本発明の化合物Iの結晶としては、例えば、図1に示される粉末X線回折パターンを示すものが好ましい。また、本発明の化合物Iの結晶としては、例えば、粉末X線回折による回折角(2θ)として、図2で表されるような特徴的ピークおよび相対強度を示す結晶が好ましい。また、本発明の化合物Iの結晶としては、例えば、5.38、8.08、10.8、13.5、15.0、16.9、17.6、20.5、21.1、22.7、23.5、26.0、27.3、27.6および30.0(°)に特徴的ピークを示す結晶が好ましい。   As the crystals of the compound I of the present invention, for example, those showing the powder X-ray diffraction pattern shown in FIG. Further, as the crystal of the compound I of the present invention, for example, a crystal showing a characteristic peak and relative intensity as shown in FIG. 2 as a diffraction angle (2θ) by powder X-ray diffraction is preferable. Examples of the crystal of the compound I of the present invention include 5.38, 8.08, 10.8, 13.5, 15.0, 16.9, 17.6, 20.5, 21.1, Crystals having characteristic peaks at 22.7, 23.5, 26.0, 27.3, 27.6 and 30.0 (°) are preferred.

さらに、本発明の化合物Iの結晶としては、上述した粉末X線回折パターンによる特徴に加え、下記の(a)〜(c):
(a)図3に示される熱分析(TG/DTA)プロフィール、具体的には、約250℃〜約270℃に2本の吸熱ピークを有する熱分析(DTA)プロフィール;
(b)図4に示される赤外吸収スペクトルパターン、例えば、1675、1614、1503、1222、1171、1033および1012cm−1付近に特徴的な吸収帯を有する赤外吸収スペクトルパターン;および
(c)融点(分解)が約246℃〜約250℃;
からなる群より選ばれる1つ以上の特徴を有する結晶が好ましい。
Further, the crystal of the compound I of the present invention includes the following (a) to (c) in addition to the above-mentioned characteristics by the powder X-ray diffraction pattern:
(A) Thermal analysis (TG / DTA) profile shown in FIG. 3, specifically, a thermal analysis (DTA) profile having two endothermic peaks at about 250 ° C. to about 270 ° C .;
(B) an infrared absorption spectrum pattern shown in FIG. 4, for example, an infrared absorption spectrum pattern having characteristic absorption bands near 1675, 1614, 1503, 1222, 1171, 1033 and 1012 cm −1 ; and (c) A melting point (decomposition) of about 246 ° C. to about 250 ° C .;
Crystals having one or more characteristics selected from the group consisting of:

このようにして得られた本願発明の化合物Iの結晶は、高い活性化血液凝固第X因子(FXaと称する場合もある。)阻害作用を示すことから、血液凝固抑制剤、血栓または塞栓の予防および/または治療剤として有用である。本願発明の化合物Iの結晶は、ヒトを含む哺乳類のための医薬、活性化血液凝固第X因子阻害剤、血液凝固抑制剤、血栓および/または塞栓の予防および/または治療剤、血栓性疾患の予防および/または治療薬、さらには脳梗塞、脳塞栓、肺梗塞、肺塞栓、心筋梗塞、狭心症、非弁膜性心房細動(Non−Valvular Atrial Fibrillation、NVAF)に伴う血栓および/または塞栓症、深部静脈血栓症、外科的手術後の深部静脈血栓症、人工弁/関節置換後の血栓形成、股関節全置換術(Total Hip Replacement、THR)後の血栓塞栓症、膝関節全置換術(Total Knee Replacement、TKR)後の血栓塞栓症、股関節骨折手術(Hip Fracture Surgery、HFS)後の血栓塞栓症、血行再建後の血栓形成および/または再閉塞、バージャー病、汎発性血管内凝固症候群、全身性炎症性反応症候群(Sytemic Inflammatory Response Syndrome、SIRS)、多臓器不全(Multiple Organ Dysfunction Syndrome、MODS)、体外循環時の血栓形成あるいは採血時の血液凝固の予防剤(本明細書において、予防とは2次予防を含む。)および/または治療剤、あるいは、これら予防剤および/または治療剤の医薬品原体として有用である。   The thus obtained crystals of Compound I of the present invention exhibit a highly activated blood coagulation factor X (sometimes referred to as FXa) inhibitory action, and thus prevent blood coagulation inhibitors, thrombus or embolism. And / or useful as a therapeutic agent. The compound I crystals of the present invention are pharmaceuticals for mammals including humans, activated blood coagulation factor X inhibitors, blood coagulation inhibitors, thrombotic and / or embolic prevention and / or treatment agents, thrombotic diseases Prophylactic and / or therapeutic agents, as well as thrombosis and / or embolism associated with cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, non-valvular atrial fibrillation (NVAF) Disease, deep vein thrombosis, deep vein thrombosis after surgical operation, thrombus formation after artificial valve / joint replacement, thromboembolism after total hip replacement (THR), total knee replacement (total knee replacement) Thromboembolism after Total Knee Replacement (TKR), Hip Fracture Surg erythromboembolism after revascularization, thrombus formation and / or reocclusion after revascularization, Buerger's disease, generalized intravascular coagulation syndrome, systemic inflammatory response syndrome (SIRS), multiple organs Prophylactic agent (in this specification, prevention includes secondary prevention) and / or therapeutic agent for insufficiency (Multiple Organ Function Syndrome, MODS), thrombus formation during extracorporeal circulation or blood coagulation during blood collection It is useful as a drug substance for a prophylactic and / or therapeutic agent.

本願発明の化合物Iの結晶を有効成分として含む医薬は、好ましくは、本願発明の化合物Iの結晶と1種または2種以上の薬学的に許容可能な担体とを含む医薬組成物の形態で提供される。本発明の医薬の投与形態は特に制限されず、経口的または非経口的に投与することができるが、好ましくは、経口的に投与される。   The medicament comprising the crystal of Compound I of the present invention as an active ingredient is preferably provided in the form of a pharmaceutical composition comprising the crystal of Compound I of the present invention and one or more pharmaceutically acceptable carriers. Is done. The dosage form of the medicament of the present invention is not particularly limited and can be administered orally or parenterally, but is preferably administered orally.

上記の医薬組成物の製造に用いる薬学的に許容可能な担体としては、例えば、賦形剤、崩壊剤ないし崩壊補助剤、結合剤、滑沢剤、コーティング剤、色素、希釈剤、基剤、溶解剤ないし溶解補助剤、等張化剤、pH調節剤、安定化剤、噴射剤または粘着剤を挙げることができるが、これらに限定されることはない。   Examples of the pharmaceutically acceptable carrier used in the production of the above pharmaceutical composition include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, Examples include, but are not limited to, a solubilizer or a solubilizer, an isotonic agent, a pH adjuster, a stabilizer, a propellant, or an adhesive.

経口投与に適する製剤の例としては、例えば、錠剤、散剤、顆粒剤、カプセル剤、溶液剤、シロップ剤、エリキシル剤、油性ないし水性の懸濁液等を例示できる。また、非経口投与に適する製剤としては、例えば、注射剤、点滴剤、坐剤、吸入剤または貼付剤を挙げることができる。   Examples of preparations suitable for oral administration include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. Examples of preparations suitable for parenteral administration include injections, drops, suppositories, inhalants, and patches.

本発明の医薬の投与量は特に限定されず、患者の年齢、体重、症状などの種々の条件に応じて適宜選択することができるが、有効成分を体重1kg当たり0.01mg〜1000mg、好ましくは0.1mg〜200mg、より好ましくは0.5mg〜100mgを、1日当り1回〜数回、症状に応じて投与することが望ましい。   The dose of the medicament of the present invention is not particularly limited and can be appropriately selected according to various conditions such as the age, weight, and symptoms of the patient. The active ingredient is 0.01 mg to 1000 mg per kg body weight, preferably It is desirable to administer 0.1 mg to 200 mg, more preferably 0.5 mg to 100 mg, once to several times per day depending on the symptoms.

以下に実施例を記載するが、本発明はこれらに限定されるものではない。   Examples are described below, but the present invention is not limited thereto.

(実施例1)N−(5−クロロピリジン−2−イル)−N−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド(化合物II)の合成
化合物IIは、特許文献1〜5に記載の方法に準じて合成した。
(Example 1) N 1 - (5-chloropyridin-2-yl) -N 2 - ((1S, 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - Synthesis of 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide (Compound II) Compound II is a method described in Patent Documents 1-5 It was synthesized according to

(実施例2)N−(5−クロロピリジン−2−イル)−N−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド p−トルエンスルホン酸塩 一水和物(化合物I)の結晶
実施例1で得た化合物4.1gを60℃にて15%含水エタノール50mLに懸濁させ、1mol/L p−トルエンスルホン酸エタノール溶液7.42mLを添加後、15%含水エタノール40mLを追加し、溶解した。その後、室温まで冷却し、1日撹拌した。析出晶を濾取し、エタノールで洗浄後、室温にて2時間減圧乾燥し、標記結晶4.7g(86%)を得た。
融点(分解)246〜250℃。
(Example 2) N 1 - (5-chloropyridin-2-yl) -N 2 - ((1S, 2R, 4S) -4 - [( dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide p-toluenesulfonate monohydrate (compound I) crystals Example 1 4.1 g of the compound obtained in the above was suspended in 50 mL of 15% aqueous ethanol at 60 ° C., and after adding 7.42 mL of 1 mol / L p-toluenesulfonic acid ethanol solution, 40 mL of 15% aqueous ethanol was added and dissolved. . Then, it cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol, and dried under reduced pressure at room temperature for 2 hours to obtain 4.7 g (86%) of the title crystals.
Melting point (decomposition) 246-250 ° C.

(試験例1)
実施例2の結晶を調製し、粉末X線測定装置を用いて結晶形の測定を実施した。
粉末X線測定の条件:線源:Cu−Kα線、電圧:40kV、電圧:20mA、装置:RINT−ULTIMA(リガク)
粉末X線回折パターンの結果を図1に、特徴的なピークおよびその相対強度を図2に示す。
(Test Example 1)
The crystal of Example 2 was prepared, and the crystal form was measured using a powder X-ray measuring apparatus.
Conditions for powder X-ray measurement: radiation source: Cu-Kα ray, voltage: 40 kV, voltage: 20 mA, apparatus: RINT-ULTIMA (Rigaku)
The results of the powder X-ray diffraction pattern are shown in FIG. 1, and characteristic peaks and their relative intensities are shown in FIG.

(試験例2)
実施例2の結晶を調整し、熱分析(TG/DTA)の測定を実施した。
熱分析(TG/DTA)測定の条件:昇温速度:10℃/分、雰囲気:窒素100mL/分、装置:TG/DTA220U(セイコーインスツルメンツ)
結果を図3に示す。実施例2の結晶は、約250℃〜約270℃に2本の吸熱ピークを有し、室温〜約150℃に2.3%の重量減少を示した。
(Test Example 2)
The crystal of Example 2 was prepared, and thermal analysis (TG / DTA) measurement was performed.
Thermal analysis (TG / DTA) measurement conditions: heating rate: 10 ° C./min, atmosphere: nitrogen 100 mL / min, apparatus: TG / DTA220U (Seiko Instruments)
The results are shown in FIG. The crystals of Example 2 had two endothermic peaks from about 250 ° C. to about 270 ° C. and showed a 2.3% weight loss from room temperature to about 150 ° C.

(試験例3)
実施例2の結晶を調整し、赤外吸収スペクトルの測定を実施した。
赤外吸収スペクトル測定の条件:測定法:KBr錠剤法、装置:FT−IR−8200(島津製作所)
赤外吸収スペクトルパターンを図4に、特徴的な吸収帯およびその強度を図5に示す。
(Test Example 3)
The crystal of Example 2 was prepared and the infrared absorption spectrum was measured.
Conditions for infrared absorption spectrum measurement: measurement method: KBr tablet method, apparatus: FT-IR-8200 (Shimadzu Corporation)
FIG. 4 shows the infrared absorption spectrum pattern, and FIG. 5 shows the characteristic absorption band and its intensity.

(試験例4)
実施例2の結晶について吸脱湿性を評価した。結晶約20mgをマイクロバランス(自動水蒸気吸着装置)中、相対湿度(RH)範囲0〜93%での経時的重量変化を測定することにより水分の吸脱着量を評価した。
(Test Example 4)
The crystal of Example 2 was evaluated for moisture absorption and desorption. The amount of moisture adsorbed / desorbed was evaluated by measuring the change in weight over time in a relative humidity (RH) range of 0 to 93% in a microbalance (automatic water vapor adsorption apparatus) of about 20 mg of crystals.

結果を図6に示す。   The results are shown in FIG.

本発明の化合物Iの結晶は、血栓性および/または塞栓性疾患の予防および/または治療薬として有用である。   The crystals of Compound I of the present invention are useful as preventive and / or therapeutic agents for thrombotic and / or embolic diseases.

Claims (8)

下記の式(I)

で表される、N−(5−クロロピリジン−2−イル)−N−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド p−トルエンスルホン酸塩 1水和物の結晶。
Formula (I) below

N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide p-toluenesulfonate monohydrate crystals.
粉末X線回折による回折角(2θ)として、5.38、8.08、10.8、13.5、15.0、16.9、17.6、20.5、21.1、22.7、23.5、26.0、27.3、27.6および30.0(°)に特徴的ピークを有する請求項1に記載の結晶。 As diffraction angles (2θ) by powder X-ray diffraction, 5.38, 8.08, 10.8, 13.5, 15.0, 16.9, 17.6, 20.5, 21.1, 22. The crystal according to claim 1 having characteristic peaks at 7, 23.5, 26.0, 27.3, 27.6 and 30.0 (°). さらに、下記の(a)〜(c):
(a)約250℃〜約270℃に2本の吸熱ピークを有する熱分析(DTA)プロフィール;
(b)1675、1614、1503、1222、1171、1033および1012cm−1付近に特徴的な吸収帯を有する赤外吸収スペクトルパターン;および
(c)融点(分解)が約246℃〜約250℃;
からなる群より選ばれる1つ以上の特徴を有する、請求項2に記載の結晶。
Further, the following (a) to (c):
(A) a thermal analysis (DTA) profile having two endothermic peaks at about 250 ° C. to about 270 ° C .;
(B) an infrared absorption spectral pattern having characteristic absorption bands near 1675, 1614, 1503, 1222, 1171, 1033 and 1012 cm −1 ; and (c) a melting point (decomposition) of about 246 ° C. to about 250 ° C .;
The crystal of claim 2 having one or more characteristics selected from the group consisting of:
請求項1〜3のいずれか1項に記載の結晶を含有する医薬。 The pharmaceutical containing the crystal | crystallization of any one of Claims 1-3. 請求項1〜3のいずれか1項に記載の結晶を含有する活性化血液凝固第X因子(FX
a)阻害剤。
Activated blood coagulation factor X (FX) containing the crystal according to any one of claims 1 to 3.
a) Inhibitors.
請求項1〜3のいずれか1項に記載の結晶を含有する血栓または塞栓の予防および/または治療剤。 A prophylactic and / or therapeutic agent for a thrombus or embolus containing the crystal according to any one of claims 1 to 3. 請求項1〜3のいずれか1項に記載の結晶を含有する脳梗塞、脳塞栓、肺梗塞、肺塞栓、心筋梗塞、狭心症、非弁膜性心房細動(NVAF)に伴う血栓および/または塞栓症、深部静脈血栓症、外科的手術後の深部静脈血栓症、人工弁/関節置換後の血栓形成、股関節全置換術(THR)後の血栓塞栓症、膝関節全置換術(TKR)後の血栓塞栓症、股関節骨折手術(HFS)後の血栓塞栓症、血行再建後の血栓形成および/または再閉塞、バージャー病、汎発性血管内凝固症候群、全身性炎症性反応症候群(SIRS)、多臓器不全(MODS)、体外循環時の血栓形成あるいは採血時の血液凝固の予防剤および/または治療剤。 A thrombosis associated with cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, non-valvular atrial fibrillation (NVAF) and / or a crystal containing the crystal according to claim 1. Or embolism, deep vein thrombosis, deep vein thrombosis after surgical operation, thrombus formation after prosthetic valve / joint replacement, thromboembolism after total hip replacement (THR), total knee replacement (TKR) Thromboembolism after hip fracture surgery (HFS), thrombosis and / or reocclusion after revascularization, Buerger's disease, generalized intravascular coagulation syndrome, systemic inflammatory response syndrome (SIRS) Agents for preventing and / or treating multiple organ failure (MODS), thrombus formation during extracorporeal circulation, or blood coagulation during blood collection. 請求項1〜3のいずれか1項に記載の結晶および薬学的に許容される担体を含有する、医薬組成物。 A pharmaceutical composition comprising the crystal according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
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WO2011115066A1 (en) 2010-03-19 2011-09-22 第一三共株式会社 Crystal of diamine derivative and method of producing same
US8901345B2 (en) 2010-07-02 2014-12-02 Daiichi Sankyo Company, Limited Process for preparation of optically active diamine derivative salt
WO2015129603A1 (en) * 2014-02-25 2015-09-03 第一三共株式会社 High-purity crystals of active blood coagulation factor x (fxa) inhibitor
CN105777779A (en) * 2014-12-16 2016-07-20 四川海思科制药有限公司 Edoxaban tosilate hydrate
CN107033163A (en) * 2015-07-16 2017-08-11 浙江海正药业股份有限公司 A kind of Yi Dushaban is to benzene methanesulfonic acid salt novel crystal forms and its preparation method and application
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011115066A1 (en) 2010-03-19 2011-09-22 第一三共株式会社 Crystal of diamine derivative and method of producing same
KR20130016225A (en) 2010-03-19 2013-02-14 다이이찌 산쿄 가부시키가이샤 Crystal of diamine derivative and method of producing same
US8541443B2 (en) 2010-03-19 2013-09-24 Daiichi Sankyo Company, Limited Crystal of diamine derivative and method of producing same
US8901345B2 (en) 2010-07-02 2014-12-02 Daiichi Sankyo Company, Limited Process for preparation of optically active diamine derivative salt
WO2015129603A1 (en) * 2014-02-25 2015-09-03 第一三共株式会社 High-purity crystals of active blood coagulation factor x (fxa) inhibitor
JPWO2015129603A1 (en) * 2014-02-25 2017-03-30 第一三共株式会社 High purity crystals of activated blood coagulation factor X (FXa) inhibitor
CN105777779A (en) * 2014-12-16 2016-07-20 四川海思科制药有限公司 Edoxaban tosilate hydrate
CN107033163A (en) * 2015-07-16 2017-08-11 浙江海正药业股份有限公司 A kind of Yi Dushaban is to benzene methanesulfonic acid salt novel crystal forms and its preparation method and application
WO2022129535A1 (en) 2020-12-18 2022-06-23 Krka, D.D., Novo Mesto Edoxaban formulation containing no sugar alcohols

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