JP2006298909A - Medicine composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicine composition and an FXa inhibitor which comprise an amide type carboxamide derivative or its salt as an active ingredient. <P>SOLUTION: The medicine composition and the FXa inhibitor comprise an amide type carboxamide derivative represented by general formula [1] (X is a group represented by formula -N= or formula -CH=; R<SP>1</SP>is a halogen atom, a lower alkyl group or the like; R<SP>2</SP>is a group represented by formula [α] or the like; Y<SP>1</SP>and Y<SP>2</SP>are the same or different and are each a group selected from a lower alkyl group, a lower alkoxy group, etc.; ring A is a phenyl group or the like) or its physiologically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition containing an amide type carboxamide derivative or a pharmacologically acceptable salt thereof as an active ingredient and an activated blood coagulation factor X (FXa) inhibitor.

  In recent years, thromboembolic diseases such as myocardial infarction, cerebral infarction, and peripheral arterial thrombosis have been increasing year by year due to the westernization of lifestyles and the arrival of an aging society, and the social importance of their treatment has increased. ing.

  Among the treatment methods for thromboembolic diseases, anticoagulation therapy is a part of medical treatment methods in the treatment and prevention of thrombosis together with fibrinolytic therapy and antiplatelet therapy. In particular, in the prevention of thrombosis, safety that can withstand long-term administration and development of reliable and appropriate anticoagulant activity are essential. Coumarin derivatives, especially warfarin potassium, are frequently used as oral anticoagulants around the world, but due to their mechanism of action, it takes a long time for the drug to appear even though the drug concentration range is narrow. Moreover, the anticoagulant ability is difficult to control because the blood half-life is very long and the individual difference in the effective dose is very large (Non-patent Documents 1 and 2), and the risk of bleeding, nausea, There are side effects such as vomiting, diarrhea, and hair loss, which are clinically very difficult to use, and the appearance of a more useful and easy-to-use anticoagulant is desired.

Also, unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, generalized intravascular coagulation syndrome, thrombus formation after replacement of prosthetic valve, after revascularization Since reocclusion of blood and thrombus formation during extracorporeal circulation is one of the important factors, increased blood clotting ability is superior in dose response, low risk of bleeding, less side effects, and oral administration. An excellent anticoagulant capable of obtaining a sufficient effect is demanded (Non-patent Document 3).
Thrombin is not only responsible for the conversion of fibrinogen to fibrin, which is the final stage of the coagulation cascade, but is also deeply involved in platelet activation and aggregation (Non-patent Document 4), and its inhibitor has long been a target for drug discovery. It was at the center of anticoagulant research. However, the thrombin inhibitor has low bioavailability after oral administration, and has a problem in safety such as showing a bleeding tendency as a side effect (Non-patent Document 5).

  FXa is a Key Enzyme located at the confluence of extrinsic and intrinsic coagulation cascade reactions, and is located upstream of thrombin in the coagulation cascade, so that inhibition of this factor is more efficient than thrombin inhibition and There is a possibility that the coagulation system can be specifically inhibited (Non-patent Document 6).

  Therefore, those that inhibit FXa, have excellent enzyme selectivity, and have high bioavailability can be controlled for long-term anticoagulant activity by oral administration, and have superior therapeutic effects compared to existing anticoagulants. Therefore, creation of an orally administrable FXa inhibitor is eagerly desired.

  As a compound showing an FXa inhibitory action, a thiobenzamide compound useful for the prevention or treatment of thrombosis and the like is known (Patent Document 1).

  On the other hand, although the following benzofuran compound is known (Non-patent Document 7), there is no description about the FXa inhibitory action of the compound.

  Furthermore, the following condensed bicyclic amide compounds having an action of inhibiting activated lymphocyte proliferation and useful as preventive or therapeutic agents for autoimmune diseases are known (Patent Document 2).

  However, this publication does not describe any FXa inhibitory action, and discloses a compound in which amide and carbamoyl are di-substituted on a condensed ring composed of pyridine and furan, but the benzene ring on the nitrogen atom of the carbamoyl is disclosed. Describes only compounds having two substituents X and Y at the same time.

WO99 / 42439 brochure International Publication No. 02/12189 Pamphlet Journal of Clinical Pharmacology, 1992, Vol. 32, p.196-209 NEW ENGLAND JOURNAL OF MEDICINE, 1991, 324, 26, 1865-1875 Thrombosis Research, 1992, Vol. 68, pp. 507-512 Osamu Matsuo, t-PA and Pro-UK, Interdisciplinary Planning, 1986, p.5-40 Biomedica Biochimica Acta, 1985, 44, 120-1210 Thrombosis Research, 1980, Vol. 19, p.339-349 Indian Journal of Heterocyclic Chemistry, 1994, Vol. 3, p. 3247-3252

  The present invention provides a pharmaceutical composition comprising an amide type carboxamide derivative having an excellent FXa inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient.

As a result of intensive studies, the present inventors have found that the following amide type carboxamide derivatives have an excellent FXa inhibitory action, and have completed the present invention.
That is, the present invention is as follows.
1.
General formula [1]:

（式中、Ｘは式：−Ｎ＝または式：−ＣＨ＝で示される基を示す。Ｙ^１およびＹ^２は、同一または異なって、水素原子、ハロゲン原子、低級アルキル基、低級アルコキシ基、ハロゲン原子置換低級アルキル基、低級アルコキシカルボニル基、カルボキシル基、低級アルキルカルバモイル基およびフェニル基から選ばれる基を示す。Ｒ^１は、水素原子、ハロゲン原子、低級アルキル基または低級アルコキシ基を示す。Ｒ^２は、式：−ＣＯ−Ｒ^２１−Ｒ^２２で示される基を示す。Ｒ^２１は、低級アルキレン基またはシクロアルカンジイル基を示す。Ｒ^２２は、

(In the formula, X represents a group represented by the formula: —N═ or the formula: —CH═. Y ¹ and Y ² are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, A halogen atom-substituted lower alkyl group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylcarbamoyl group and a phenyl group, and R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. ² represents a group represented by the formula: —CO—R ²¹ —R ²² , R ²¹ represents a lower alkylene group or a cycloalkanediyl group, and R ²² represents

を示す。Ｒ^２３およびＲ^２４は、同一または異なって、低級アルキル基または低級アルキル基で置換されていてもよいアミノ低級アルキル基を示すか、あるいはＲ^２３及びＲ^２４が互いに末端で結合して隣接する式：−Ｎ−Ｃ（＝Ｏ）−で示される基とともに置換されていてもよい含窒素飽和異項環基を形成する。Ｒ^２５およびＲ^２６は、同一または異なって、低級アルキル基または低級アルキル基で置換されていてもよいアミノ低級アルキル基を示すか、あるいはＲ^２５及びＲ^２６が互いに末端で結合して隣接する窒素原子とともに置換されていてもよい含窒素飽和異項環基を形成する。環Ａは、芳香族炭化水素環、単環式複素芳香環または縮合チオフェン環を示す。）により表されるアミド型カルボキサミド誘導体またはその薬理的に許容しうる塩、および薬理的に許容される担体からなる医薬組成物。
２．
一般式［１］：

Indicates. R ²³ and R ²⁴ are the same or different and represent a lower alkyl group or an amino lower alkyl group which may be substituted with a lower alkyl group, or R ²³ and R ²⁴ are adjacent to each other at the end. : Forms a nitrogen-containing saturated heterocyclic group which may be substituted together with the group represented by —N—C (═O) —. R ²⁵ and R ²⁶ are the same or different and each represents a lower alkyl group or an amino lower alkyl group which may be substituted with a lower alkyl group, or R ²⁵ and R ²⁶ are bonded to each other at the end and adjacent nitrogen atoms. A nitrogen-containing saturated heterocyclic group which may be substituted with an atom is formed. Ring A represents an aromatic hydrocarbon ring, a monocyclic heteroaromatic ring or a condensed thiophene ring. And a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising a pharmacologically acceptable carrier.
2.
General formula [1]:

（式中、Ｘは式：−Ｎ＝または式：−ＣＨ＝で示される基を示す。Ｙ^１およびＹ^２は、同一または異なって、水素原子、ハロゲン原子、低級アルキル基、低級アルコキシ基、ハロゲン原子置換低級アルキル基、低級アルコキシカルボニル基、カルボキシル基、低級アルキルカルバモイル基およびフェニル基から選ばれる基を示す。Ｒ^１は、水素原子、ハロゲン原子、低級アルキル基または低級アルコキシ基を示す。Ｒ^２は、式：−ＣＯ−Ｒ^２１−Ｒ^２２で示される基を示す。Ｒ^２１は、低級アルキレン基またはシクロアルカンジイル基を示す。Ｒ^２２は、

(In the formula, X represents a group represented by the formula: —N═ or the formula: —CH═. Y ¹ and Y ² are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, A halogen atom-substituted lower alkyl group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylcarbamoyl group and a phenyl group, and R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. ² represents a group represented by the formula: —CO—R ²¹ —R ²² , R ²¹ represents a lower alkylene group or a cycloalkanediyl group, and R ²² represents

を示す。Ｒ^２３およびＲ^２４は、同一または異なって、低級アルキル基または低級アルキル基で置換されていてもよいアミノ低級アルキル基を示すか、あるいはＲ^２３及びＲ^２４が互いに末端で結合して隣接する式：−Ｎ−Ｃ（＝Ｏ）−で示される基とともに置換されていてもよい含窒素飽和異項環基を形成する。Ｒ^２５およびＲ^２６は、同一または異なって、低級アルキル基または低級アルキル基で置換されていてもよいアミノ低級アルキル基を示すか、あるいはＲ^２５及びＲ^２６が互いに末端で結合して隣接する窒素原子とともに置換されていてもよい含窒素飽和異項環基を形成する。環Ａは、芳香族炭化水素環、単環式複素芳香環または縮合チオフェン環を示す。）により表されるアミド型カルボキサミド誘導体またはその薬理的に許容しうる塩を有効成分として含有するＦＸａ阻害剤。
３．
血栓ならびに塞栓によって引き起こされる疾患の予防または治療薬である前記２に記載のＦＸａ阻害剤。
４．
Ｎ−（５−クロロピリジン−２−イル）−５−メトキシ−２−（｛［トランス−４−（３−オキソモルホリン−４−イル）シクロヘキシル］カルボニル｝アミノ）ベンズアミドまたはその薬理的に許容しうる塩を有効成分として含有する活性化血液凝固第Ｘ因子阻害剤。
本発明の有効成分化合物［１］またはそれらの薬理的に許容しうる塩のうち好ましい化合物は、以下の通りである。
〔ｉ〕環Ａが、ベンゼン、ナフタレン、ピリジン、フラン、チオフェン、ピラゾール、ベンゾチオフェンまたはチエノピリジンである化合物。
〔ｉｉ〕Ｒ^２が、

Indicates. R ²³ and R ²⁴ are the same or different and represent a lower alkyl group or an amino lower alkyl group which may be substituted with a lower alkyl group, or R ²³ and R ²⁴ are adjacent to each other at the end. : Forms a nitrogen-containing saturated heterocyclic group which may be substituted together with the group represented by —N—C (═O) —. R ²⁵ and R ²⁶ are the same or different and each represents a lower alkyl group or an amino lower alkyl group which may be substituted with a lower alkyl group, or R ²⁵ and R ²⁶ are bonded to each other at the end and adjacent nitrogen atoms. A nitrogen-containing saturated heterocyclic group which may be substituted with an atom is formed. Ring A represents an aromatic hydrocarbon ring, a monocyclic heteroaromatic ring or a condensed thiophene ring. The FXa inhibitor which contains the amide type | mold carboxamide derivative represented by this, or its pharmacologically acceptable salt as an active ingredient.
3.
3. The FXa inhibitor according to 2 above, which is a preventive or therapeutic agent for diseases caused by thrombi and emboli.
4).
N- (5-chloropyridin-2-yl) -5-methoxy-2-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) benzamide or a pharmaceutically acceptable salt thereof An activated blood coagulation factor X inhibitor comprising a salt that can be obtained as an active ingredient.
Among the active ingredient compounds [1] of the present invention or pharmacologically acceptable salts thereof, preferred compounds are as follows.
[I] A compound in which ring A is benzene, naphthalene, pyridine, furan, thiophene, pyrazole, benzothiophene or thienopyridine.
[Ii] R ² is

であり、Ｒ^２２が、

And R ²² is

であり、

And

が

But

である〔ｉ〕記載の化合物。
〔ｉｉｉ〕Ｒ^１がハロゲン原子または低級アルキル基であり、Ｒ^２が

The compound according to [i].
[Iii] R ¹ is a halogen atom or a lower alkyl group, and R ² is

であり、Ｒ^２２が

And R ²² is

であり、

And

が

But

であり、Ｙ^１およびＹ^２が、同一または異なって、水素原子、ハロゲン原子、低級アルキル基、低級アルコキシ基およびカルボキシル基から選ばれる基である〔ｉ〕記載の化合物。
〔ｉｖ〕

And Y ¹ and Y ² are the same or different and are a group selected from a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group and a carboxyl group, [i].
[Iv]

が

But

である〔ｉｉｉ〕記載の化合物。

The compound of [iii].

Hereinafter, the active ingredient compound [1] of the present invention will be described in detail.
In the definition of the general formula in the present specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.

  Accordingly, examples of the “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1 , 2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methyl Propyl, 1-ethyl-2-methylpropyl and the like. Among these, those having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are common.

  The “lower alkoxy group” means a substituent in which an oxygen atom is bonded to the lower alkyl group. Among these, those having 1 to 4 carbon atoms, that is, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, and tert-butoxy group are common.

  The “lower alkylene group” is, for example, a linear or branched alkylene having 1 to 6 carbon atoms, and specifically includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like. Of these, alkylene having 1 to 5 carbon atoms is common.

  Examples of the “cycloalkanediyl group” include a 3- to 7-membered cycloalkanediyl group, such as a 1,4-cyclohexanediyl group.

  Examples of the “aromatic hydrocarbon ring” include benzene, naphthalene, anthracene, phenanthrene, and the like, and condensed rings are also included. Of these, benzene or naphthalene is common.

  “Monocyclic heteroaromatic ring” means a monocyclic heteroaromatic ring having 1 to 4 identical or different heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. ˜7 membered heterocycles are common. Specific examples include pyridine, furan, thiophene, pyrazole, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyridazine, pyrimidine, and pyrazine.

  The “fused thiophene ring” means a ring obtained by condensing a thiophene ring and a cyclic compound, and includes benzothiophene or thienopyridine.

  The “nitrogen-containing saturated heterocyclic group” means a saturated ring group having 1 to 4 heteroatoms, and the ring may have an oxygen atom and / or a sulfur atom in addition to a nitrogen atom. Of these, a 4- to 14-membered saturated heterocyclic group having only a nitrogen atom as a heteroatom, or having a nitrogen atom and an oxygen atom as a heteroatom is common, and a condensed ring is also included. Specific examples include imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, homopiperidyl, pyrrolidinyl, oxazolidinyl and the like.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably a fluorine atom, a chlorine atom, and a bromine atom are mentioned.

  As the pharmacologically acceptable salt of the active ingredient compound [1] of the present invention, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or formic acid, Salts with organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or Salts with acidic amino acids such as aspartic acid and glutamic acid, salts with metals such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine and ethanolamine, or bases such as lysine and ornithine And salts with sexual amino acids. The active ingredient compound [1] of the present invention may be a quaternary salt, and the active ingredient compound of the present invention includes a quaternary salt.

  In addition, the active ingredient compound [1] of the present invention includes inner salts, hydrates, solvates and polymorphs.

  Further, when the active ingredient compound [1] of the present invention has an asymmetric carbon, an optical isomer exists, but the active ingredient compound [1] of the present invention includes one or a mixture of these isomers. Further, when the active ingredient compound [1] of the present invention has a double bond or a cycloalkanediyl group having two or more substituents on the ring, a cis isomer or a trans isomer may exist, The active ingredient compound [1] of the present invention includes one or a mixture of these isomers.

The active ingredient compound [1] of the present invention also includes prodrugs of the above compounds. Examples of the prodrug include those obtained by protecting a functional group such as amino and carboxy in the compound [1] with a commonly used protecting group.
The active ingredient compound of the present invention can be produced by the following method.

[Method A]
The active ingredient compound [1] of the present invention has the general formula [2]:

（式中、記号は前記と同一意味を有する）で示されるアミノ化合物と一般式［３］：
Ｒ^２−ＯＨ ［３］
（式中、記号は前記と同一意味を有する）で示されるカルボン酸化合物またはそのカルボキシル基における反応性誘導体とを反応させることにより製造することができる。

(Wherein the symbols have the same meaning as described above) and the general formula [3]:
R ² —OH [3]
(Wherein the symbols have the same meaning as described above) or a reactive derivative at the carboxyl group thereof can be produced by reacting.

[Method B]
Further, the active ingredient compound [1] of the present invention has the general formula [4]:

（式中、Ｒ^３は低級アルキル基であり、その他の記号は前記と同一意味を有する）で示される化合物と一般式［５］：

Wherein R ³ is a lower alkyl group, and the other symbols have the same meaning as described above, and the general formula [5]:

（式中、記号は前記と同一意味を有する）で示される化合物を反応させることにより製造することができる。

(Wherein the symbols have the same meaning as described above) can be produced by reacting them.

  In addition, the compound [1] synthesized by the above method [A] or [B] is appropriately subjected to alkylation reaction, reductive alkylation reaction, amidation reaction, sulfonylamidation reaction, arylation reaction, reduction as necessary. It can also be produced by interconversion to another compound [1] by reaction, dealkylation reaction, hydrolysis reaction, quaternary amination reaction, amino group and carboxyl group protection reaction and deprotection reaction, and the like.

[Raw material production method: production method of compound [2]]
Compound [2] has the general formula [7]:

（式中、記号は前記と同一意味を有する）で示される化合物またはそのカルボキシル基における反応性誘導体と化合物［５］とを反応させて一般式［６］：

(Wherein the symbols have the same meanings as described above) or a reactive derivative of the carboxyl group thereof and compound [5] are reacted with general formula [6]:

（式中、記号は前記と同一意味を有する）で示される化合物を製し、次いで、化合物［６］のニトロ基を還元することにより製造することができる。

(Wherein the symbols have the same meaning as described above), and then the nitro group of compound [6] is reduced.

  In addition, the compound [2] is represented by the general formula [10]:

（式中、記号は前記と同一意味を有する）で示される化合物と一般式［１１］：
Ｌ−ＣＯＯＺ ［１１］
（式中、Ｌは遊離基を表し、Ｚはカルボキシル基の保護基を意味する）で示される化合物を反応させ、一般式［９］：

(Wherein the symbols have the same meaning as described above) and the general formula [11]:
L-COOZ [11]
(Wherein L represents a free radical, Z means a protecting group for a carboxyl group), and a compound represented by the general formula [9]:

（式中、記号は前記と同一意味を有する）で示される化合物を製し、分子内閉環反応に供して一般式［８］：

(Wherein the symbols have the same meaning as described above), and subjected to an intramolecular ring-closing reaction, the general formula [8]:

（式中、記号は前記と同一意味を有する）で示される化合物を製し、化合物［５］を反応させることにより製造することもできる。

(Wherein the symbols have the same meaning as described above) can be produced and reacted by reacting compound [5].

[Raw material production method: production method of compound [4]]
Compound [4] has the general formula [12]:

（式中、記号は前記と同一意味を有する）で示される化合物と化合物［３］またはそのカルボキシル基における反応性誘導体とを反応させることにより製造することができる。
上記［Ａ］法〜［Ｂ］法は以下のようにして実施することができる。

(Wherein the symbols have the same meaning as described above) and compound [3] or a reactive derivative of the carboxyl group thereof can be produced.
The above [A] method to [B] method can be carried out as follows.

[Method A]
The step of producing the compound [1] using the compound represented by [3] for the compound [2] can be carried out according to a usual amidation method. For example, the reaction may be carried out by reacting compound [2] with compound [3] or a reactive derivative at the carboxyl group of compound [3], or a salt thereof in the presence or absence of a condensing agent, and optionally in the presence of a deoxidizing agent. Can be carried out in a suitable solvent. As the condensing agent, N, N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3- (dimethylaminopropyl) carbodiimide (EDC) or its hydrochloride, carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA) ), Diethyl cyanophosphate (DEPC), etc., a normal condensing agent can be suitably used, in particular, DCC, EDC or its hydrochloride can be more suitably used as the reactive derivative of compound [3]. Any of those commonly used for condensation can be used, for example, acid halides, mixed acid anhydrides, active esters, etc. As activators that can be used to convert compound [3] to reactive derivatives , Thionyl chloride, thionyl bromide, oxalyl chloride, 1-hydroxysuccini Activating agents using N-hydroxyamine compounds such as 1-hydroxybenzotriazole and phenolic compounds such as p-nitrophenol, and thionyl chloride, oxalyl chloride, 1-hydroxysuccinimide, 1-hydroxy Benzotriazole, etc. can be preferably used, in particular, the acid chloride method can be more suitably used as a salt when the compound [3] or the reactive derivative at the carboxyl group of the compound [3] forms a salt. For example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. can be used, and depending on the applied method, a deoxidizing agent can be used. This reaction can be carried out in the presence of a base or using these bases as a solvent. Inorganic bases include alkali carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate, alkaline earth metals such as calcium carbonate, sodium hydrogen carbonate, and carbonate. Examples include alkali metal hydrogen carbonates such as potassium hydrogen, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide. Examples of the organic base include tri-lower amines such as triethylamine, tributylamine, and diisopropylethylamine. Alkylamines, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undeca Tertiary amines such as 7-ene, N, N-dimethylaniline, N, N-diethylaniline, 4- Examples thereof include amines such as dimethylaminopyridine, pyridine, lutidine, collidine and the like. In particular, it is preferable to use triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and pyridine. This reaction is carried out in the presence or absence of a solvent, preferably in the presence of a solvent. The solvent is not limited as long as it is an inert solvent that does not hinder the reaction, for example, halogen solvents such as chloroform, dichloromethane, dichloroethane, aromatic hydrocarbon solvents such as benzene, toluene, xylene, diethyl ether, Ether solvents such as diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, ester solvents such as ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazo Amide solvents such as lysine, nitrile solvents such as acetonitrile, dimethyl sulfoxide, pyridine, lutidine, etc., and if necessary, two or more mixed solvents of these solvents and combinations of these solvents with water Depending on how you apply Yichun is preferable to select. In particular, dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, pyridine and the like are preferable, and dichloromethane, chloroform, N , N-dimethylformamide and pyridine are more preferable. This reaction can be carried out widely under cooling to heating. For example, the reaction can be suitably carried out at −10 ° C. to the boiling point of the reaction mixture, in particular, under ice cooling to 60 ° C.

[Method B]
In the step of producing the compound [1] from the compounds [4] and [5], the mixture of the compounds [4] and [5] is heated in a suitable solvent or without solvent, or the compound [5] is trimethylaluminum. The reaction can be carried out by reacting with the compound [4] after preparing the corresponding aluminum amide compound by the method, but the method using aluminum amide is preferred. The solvent is not limited as long as it is an inert solvent that does not interfere with the reaction. For example, halogen solvents such as chloroform, dichloromethane, dichloroethane, aromatic hydrocarbon solvents such as benzene, toluene, xylene, diethyl ether, diisopropyl Ether solvents such as ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, hexane And hydrocarbon solvents such as dimethyl sulfoxide, pyridine, lutidine, and the like, and two or more mixed solvents of these solvents as necessary, but are preferably selected according to the method to be applied. In particular, dichloromethane, chloroform, toluene, xylene, and hexane are preferable. As a reagent used in the same manner as trimethylaluminum, tri-lower alkylaluminum, diethyldihydroaluminum sodium and the like can be suitably used. This reaction can be carried out widely under cooling to heating. For example, the reaction can be suitably carried out at −10 ° C. to the boiling point of the reaction mixture, in particular, under ice cooling to 60 ° C.

  Further, after carrying out the method [A] or [B], when there is a moiety capable of further reaction in the compound represented by the compound [1] obtained (for example, mainly an amine protecting group, alcohol , Phenolic OH, ester, carboxylic acid, nitro, halogen, etc.) can be produced by performing the following reactions and the like as necessary and interconverting to produce the desired compound [1]. .

  Of the interconversions that are performed as necessary, alkylation, reductive alkylation, amidation, sulfonylamidation, arylation, reduction, dealkylation, hydrolysis, quaternary The amination reaction, amino group and carboxyl group protection reaction, and deprotection reaction can be performed as follows.

  The alkylation reaction can be carried out according to a conventional method as necessary. For example, this reaction can be carried out by reacting compound [1] with an alkyl halide such as alkyl chloride, alkyl bromide or alkyl iodide in the presence or absence of a base in an appropriate solvent. it can. Examples of the base used at this time include inorganic bases and organic bases. Examples of inorganic bases include alkali carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkali metals such as sodium bicarbonate and potassium bicarbonate, and hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide. Examples of the organic base include tri-lower alkylamines such as triethylamine, tributylamine, and diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4]. .3.0] tertiary amines such as non-5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, lutidine, collidine and the like can be used. In particular, it is preferable to use an alkali metal carbonate such as sodium carbonate, potassium carbonate or cesium carbonate, triethylamine, diisopropylethylamine, pyridine or the like. In this reaction, alkali metal iodides such as lithium iodide, sodium iodide and potassium iodide may be added, and the reaction may proceed smoothly. The solvent is not limited as long as it is an inert solvent that does not hinder the reaction. For example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, etc. Amide solvents such as N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone, nitrile solvents such as acetonitrile, alcohol solvents such as methanol, ethanol and propanol, dimethyl sulfoxide, pyridine and lutidine In addition, two or more mixed solvents of these solvents can be mentioned as necessary, but it is preferable to select appropriately according to the method to be applied. In particular, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, ethanol, dimethyl sulfoxide and the like are preferable, and N, N-dimethylformamide, acetonitrile, ethanol And a mixed solvent thereof is more preferable. This reaction can be carried out widely under cooling to heating, and particularly preferably at -10 ° C to the boiling point of the reaction mixture.

  The reductive alkylation reaction can be carried out according to a conventional method as necessary. For example, this reaction is carried out by reacting compound [1] with a corresponding carbonyl compound in an appropriate solvent under the presence of an appropriate metal hydride reducing agent or catalytic hydrogen reduction in the presence of a metal catalyst. Can be implemented. The metal hydride reducing agent is not particularly limited as long as it is normally used, but a reducing agent that does not affect the amide bond is preferable, such as sodium borohydride, sodium triacetoxyborohydride, cyanohydrogenation. Sodium boron or the like can be suitably used. In this reaction, an organic acid such as acetic acid or a mineral acid such as hydrochloric acid may be added, and the reaction may proceed smoothly by adding these. Further, when an amine that forms a salt with a mineral acid such as hydrochloric acid is used as the compound [1], an appropriate neutralizing agent, for example, an organic base such as triethylamine or an alkali metal acetate such as sodium acetate In some cases, the reaction may proceed smoothly. The solvent is not particularly limited as long as it is an inert solvent that does not interfere with the reaction. For example, halogen solvents such as chloroform, dichloromethane, dichloroethane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc. Ether solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, amide solvents such as 1,3-dimethyl-2-imidazolidinone, nitrile solvents such as acetonitrile, benzene, toluene, xylene, etc. Aromatic hydrocarbon solvents, alcohol solvents such as methanol, ethanol, and propanol, water, etc., and two or more mixed solvents of these solvents as necessary can be used, but they are appropriately selected according to the method to be applied. It is preferable to do this. In particular, dichloromethane, dichloroethane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, propanol and the like are preferable, and dichloromethane, dichloroethane, and tetrahydrofuran are more preferable. This reaction can be carried out widely under cooling to heating, for example, suitably from −10 ° C. to the boiling point of the reaction mixture, especially under ice cooling to room temperature. Moreover, this reaction can be similarly performed by a catalytic hydrogen reduction reaction in the presence of a metal catalyst. As the metal catalyst, palladium-carbon, platinum-carbon, platinum oxide, Raney nickel, or the like can be used. In this reaction, an organic acid such as acetic acid or a mineral acid such as hydrochloric acid may be added, and the reaction may proceed smoothly by adding these. Further, when an amine that forms a salt with a mineral acid such as hydrochloric acid is used as the compound [1], an appropriate neutralizing agent, for example, an organic base such as triethylamine or an alkali metal acetate such as sodium acetate In some cases, the reaction may proceed smoothly. The solvent is not limited as long as it is an inert solvent that does not hinder the reaction. For example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, etc. Amide solvents such as N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone, aromatic hydrocarbon solvents such as benzene, toluene and xylene, alcohol solvents such as methanol, ethanol and propanol, Water or the like and, if necessary, two or more mixed solvents of these solvents can be used, but it is preferable to select appropriately according to the method to be applied. In particular, tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol and the like are preferable, and tetrahydrofuran, methanol, ethanol and the like are more preferable. This reaction can be carried out widely under cooling to heating, for example, suitably from −10 ° C. to the boiling point of the reaction mixture, especially under ice cooling to room temperature.

  The amidation reaction is performed according to a conventional method as necessary. For example, the amidation reaction can be performed in the same manner as the reaction of the compound [2] and the compound [3].

  The sulfonylamidation reaction can be carried out according to a conventional method as necessary. For example, this reaction can be carried out by reacting compound [1] with an alkylsulfonic acid halide which may have a substituent, in the presence or absence of a base, in an appropriate solvent. The amidation reaction of [2] and compound [3] can be carried out at the same deoxidizing agent, solvent, and reaction temperature.

  The arylation reaction can be carried out by a conventional method as necessary. For example, this reaction can be carried out by reacting compound [1] with an aryl halide in a suitable solvent in the presence or absence of a suitable base. As the base, any of an inorganic base and an organic base can be used. Examples of the inorganic base include alkali metals such as sodium carbonate, potassium carbonate, and cesium carbonate; alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate; and examples of the organic base include triethylamine and tributylamine. , Tri-lower alkylamines such as diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5 4.0] tertiary amines such as undec-7-ene, amines such as N, N-dimethylaniline, N, N-diethylaniline, 4-dimethylaminopyridine, pyridine, lutidine, collidine, etc. Can do. In particular, it is preferable to use triethylamine, diisopropylethylamine, potassium carbonate or the like. This reaction is carried out in the presence or absence of a solvent, preferably in the presence of a solvent. The solvent is not limited as long as it is an inert solvent that does not hinder the reaction. For example, aromatic hydrocarbon solvents such as benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2- Ether solvents such as dimethoxyethane, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, nitrile solvents such as acetonitrile, methanol, ethanol, Examples thereof include alcohol solvents such as propanol and butanol, dimethyl sulfoxide, pyridine, lutidine and the like, and, if necessary, two or more of these solvents. Xylene, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, ethanol, butanol and the like are preferable, and tetrahydrofuran, N, N-dimethylacetamide and butanol are particularly preferable. More preferred. This reaction can be carried out widely under cooling to heating. For example, it can be suitably carried out at −10 ° C. to the boiling point of the reaction mixture, particularly from room temperature to the boiling point of the reaction mixture. Moreover, you may implement by the palladium coupling method.

  The reduction reaction can be carried out according to a conventional method as necessary. For example, this reaction can be carried out by reacting compound [1] with hydrogen in a suitable solvent in the presence of a suitable reducing agent or metal catalyst. The reducing agent is not particularly limited as long as it is usually used, but metal hydride reducing agents such as lithium aluminum hydride, lithium borohydride and sodium borohydride, metals such as zinc, iron and tin, or A metal salt such as tin chloride can be preferably used, and a metal salt such as tin or a metal salt such as tin chloride can be more preferably used. In addition, the metal catalyst used in the hydrogenation reaction is not particularly limited as long as it is usually used, but palladium-carbon, Raney nickel, Raney cobalt, platinum oxide, etc. can be suitably used, and a metal such as Raney nickel can be used. It can be used more suitably. Moreover, depending on the method to be applied, the reaction may proceed smoothly by reacting in the presence of a mineral acid such as hydrochloric acid in the presence of acid. The solvent used for the reaction with the metal hydride reducing agent is not limited as long as it is an inert solvent that does not interfere with the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane Solvents, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, aromatic hydrocarbon solvents such as benzene, toluene, xylene, methanol, Alcohol solvents such as ethanol and propanol, water, and the like, and two or more mixed solvents of these solvents as necessary can be used, but it is preferable to select appropriately according to the method to be applied. The solvent used in the reaction with a metal salt such as zinc, iron or tin or a metal salt such as tin chloride is not limited as long as it is an inert solvent that does not interfere with the reaction. For example, water, methanol, ethanol, propanol, etc. Alcohol solvents, ester solvents such as ethyl acetate, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ether solvents such as 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, 1, Amide solvents such as 3-dimethyl-2-imidazolidinone, nitrile solvents such as acetonitrile, aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like, and if necessary, two or more of these solvents A mixed solvent can be used, but it is appropriately selected depending on the method to be applied. Preference is. In particular, ethyl acetate, water, or a mixed solvent of water and an alcohol solvent, an ether solvent, an amide solvent, a nitrile solvent, or the like is preferable. The solvent used in the hydrogenation reaction in the presence of a metal catalyst is not particularly limited as long as it is an inert solvent that does not interfere with the reaction. For example, alcohol solvents, ether solvents, aliphatic hydrocarbon solvents, aromatic carbonization Hydrogen solvent, amide solvent, ester solvent such as ethyl acetate, organic acid solvent such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc. and mixed solvent of two or more of these solvents as necessary Although it can be used, it is preferable to select appropriately according to the method to be applied. This reaction can be carried out widely under cooling to heating, for example, suitably from −10 ° C. to the boiling point of the reaction mixture. The pressure of hydrogen used in the catalytic hydrogen reduction reaction is usually about 1 to about 100 atmospheres. The reaction time of this reaction varies depending on the activity of the reducing agent and catalyst used and the amount used, but is usually about 10 minutes to 24 hours.

  In addition, the dealkylation reaction can be carried out according to a conventional method as necessary. For example, this reaction can be carried out by reacting compound [1] with a suitable dealkylating agent in a suitable solvent or without solvent. The dealkylating agent is not particularly limited as long as it is normally used, but boron tribromide, boron trichloride, iodotrimethylsilane, aluminum (III) chloride, pyridinium chloride, etc. can be suitably used. In particular, it is preferable to use boron tribromide, iodotrimethylsilane or the like. The solvent is not limited as long as it is an inert solvent that does not interfere with the reaction. For example, halogen solvents such as chloroform, dichloromethane, dichloroethane, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3 -Amide solvents such as dimethyl-2-imidazolidinone, nitrile solvents such as acetonitrile, etc., and if necessary, two or more mixed solvents of these solvents can be mentioned, but depending on the application method, It is preferable to select. This reaction can be carried out widely under cooling to heating, particularly preferably from -78 ° C to the boiling point of the reaction mixture.

Moreover, a hydrolysis reaction can be suitably performed by a conventional method.
Further, the quaternary amination reaction is performed as necessary, but can be performed in the same manner as the alkylation reaction.
Moreover, although the protection reaction and deprotection reaction of an amino group and a carboxyl group are performed as needed, arbitrary well-known methods can be used suitably.

[Raw material production method: production method of compound [2]]
The step of producing compound [6] by reacting compound [7] or a reactive derivative at the carboxyl group with compound [5] is carried out in the same manner as the step of reacting compounds [2] and [3]. can do.

  Next, the step of producing the compound [2] by reducing the nitro group of the obtained compound [6] can be carried out by the same method as the above reduction reaction.

  The step of producing compound [9] by reacting compound [10] with compound [11] can be carried out in the same manner as the step of reacting compounds [2] and [3].

  In the step of obtaining compound [8] by intramolecular ring closure of compound [9], the compound [9] is converted to a reactive derivative by using an activator in the presence or absence of a condensing agent as necessary. And can be carried out in a suitable solvent in the presence or absence of a deoxidizer. As the condensing agent, N, N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3- (dimethylaminopropyl) carbodiimide (EDC) or its hydrochloride, carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA) ), Diethyl cyanophosphate (DEPC), etc., a normal condensing agent can be preferably used, and in particular, DCC, EDC, or a hydrochloride thereof can be more preferably used as a reactive derivative of compound [9]. Any of those commonly used for condensation can be used, for example, acid halides, mixed acid anhydrides, active esters, etc. As activators that can be used to convert compound [9] to reactive derivatives , Thionyl chloride, oxalyl chloride, etc. can be suitably used. In addition, a deoxidizing agent can be used depending on a method to be applied, and an inorganic base or an organic base can be used as the deoxidizing agent. The reaction may proceed smoothly in the presence of a base or by using these bases as a solvent.Inorganic bases include alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and calcium carbonate. Examples include alkaline earth metal carbonates, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide. , Tri-lower alkylamines such as triethylamine, tributylamine, diisopropylethylamine, 1,4-diazabi Tertiary amines such as b [2.2.2] octane, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene N, N-dimethylaniline, N, N-diethylaniline, amines such as 4-dimethylaminopyridine, pyridine, lutidine, collidine, etc. In particular, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc. The reaction is carried out in the presence or absence of a solvent, preferably in the presence of a solvent, which is an inert solvent that does not interfere with the reaction. If there is no limitation, for example, a halogen-based solvent such as chloroform, dichloromethane or dichloroethane, or a good solvent such as benzene, toluene or xylene. Aromatic hydrocarbon solvents, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, ester solvents such as ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide Amide solvents such as 1,3-dimethyl-2-imidazolidinone, nitrile solvents such as acetonitrile, dimethyl sulfoxide, pyridine, lutidine, etc., and if necessary, a mixture of two or more of these solvents In addition, a combination of these solvents and water can be mentioned, but it is preferable to select appropriately according to the method to be applied. In particular, dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, pyridine and the like are preferable, and dichloromethane, chloroform, N , N-dimethylformamide and pyridine are more preferable. This reaction can be carried out widely under cooling to heating. For example, the reaction can be suitably carried out at −10 ° C. to the boiling point of the reaction mixture, in particular, under ice cooling to 60 ° C.

  The step of reacting compound [8] with compound [5] to produce compound [2] can be carried out in the same manner as the step of reacting compounds [4] and [5].

[Raw material production method: production method of compound [4]]
The step of producing compound [4] by reacting compound [12] with compound [3] or a reactive derivative at its carboxyl group is carried out in the same manner as the step of reacting compounds [2] and [3]. can do.

  The active ingredient compound of the present invention thus obtained can be isolated and purified by a known method in the field of organic synthetic chemistry such as recrystallization and column chromatography.

  Since the active ingredient compound [1] of the present invention or a pharmacologically acceptable salt thereof has an excellent FXa inhibitory action, it can be used in mammals (eg, humans, monkeys, rabbits, dogs, cats, pigs, horses, cows). , Mice, rats, guinea pigs, etc.) for various diseases caused by thrombus and embolism such as stable angina, unstable angina, cerebral thrombus, cerebral infarction, cerebral embolism, transient ischemic attack ( TIA), ischemic cerebrovascular disorders such as cerebral vasospasm after subarachnoid hemorrhage, ischemic heart disease due to coronary thrombus formation, congestive chronic heart failure, myocardial infarction, acute myocardial infarction, pulmonary infarction, pulmonary embolism, pulmonary vascular disorder , Economy class syndrome, kidney disease (diabetic nephropathy, chronic glomerulonephritis, IgA nephropathy, etc.), thrombus formation with atherosclerosis, peripheral artery occlusion, peripheral vein occlusion, Buerger's disease, deep vein Embolism, generalized intravascular coagulation syndrome (DIC), thrombus formation after artificial blood vessel surgery or prosthetic valve or joint replacement, intermittent claudication, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous Thrombus formation and re-occlusion after revascularization such as tubular coronary artery reopening therapy (PTCR), systemic inflammatory response syndrome (SIRS), multiple organ failure (MODS), thrombus formation during extracorporeal circulation, blood clotting at the time of blood collection It is useful for the prevention or treatment of diabetic circulatory disorder, rejection at the time of transplantation, organ protection at the time of transplantation or improvement of function.

  In addition, the active ingredient compound of the present invention has an excellent FXa inhibitory action, and at the same time, has the characteristics that toxicity is reduced and side effects (such as bleeding) of existing anticoagulants are hardly observed.

An FXa inhibitor having a small distribution volume (in-body drug amount / blood concentration) does not substantially show side effects such as phospholipidosis and hepatotoxicity. Therefore, an FXa inhibitor having a small distribution volume, particularly an FXa inhibitor having a distribution volume of 0.1 to 3.0 L / kg and having an FXa inhibitory action (IC ₅₀ ) of 100 nM or less, causes side effects such as phospholipidosis and hepatotoxicity. Is useful as a therapeutic agent for thrombosis.

  The active ingredient compound [1] of the present invention or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmacologically acceptable carrier. Pharmacologically acceptable carriers include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine) ), Lubricants (magnesium stearate, talc, polyethylene glycol, silica), disintegrants (potato starch), wetting agents (sodium lauryl sulfate), and the like.

  The active ingredient compound [1] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and can be used as an appropriate pharmaceutical preparation. Examples of suitable pharmaceutical preparations for oral administration include solid preparations such as tablets, granules, capsules, powders, solution preparations, suspension preparations, and emulsion preparations. Appropriate pharmaceutical preparations for parenteral administration include suppositories, injections or infusion preparations using distilled water for injection, physiological saline or aqueous glucose solution, or inhalants.

  The dose of the active ingredient compound [1] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, condition or type / degree of disease, but is usually about 1 per day. It is preferably about 0.1 to 50 mg / kg, particularly about 0.1 to 30 mg / kg.

  Hereinafter, the present invention will be described in detail with reference to experimental examples, preparation examples, and reference examples, but the present invention is not limited thereto.

Experimental Example 1: FXa inhibitory action In a 100 mM Tris buffer (pH 8.4) containing 200 mM sodium chloride and 0.1% bovine serum albumin, the chromogenic substrate S-2222 is 0.625 mM (final concentration 0.5 mM). 25 μl of a test compound solution dissolved in a buffer containing 10% dimethyl sulfoxide was added to 200 μl of the substrate solution dissolved in 1. To the control group, 25 μl of a buffer containing 10% dimethyl sulfoxide was added instead of the test compound solution. After preheating at 37 ° C. for 3 minutes, 25 μl of 0.5 U / ml human FXa (Enzyme Research Laboratories, Inc.) dissolved in buffer was added (final concentration 0.05 U / ml) to initiate the reaction. Under the reaction at 37 ° C. for 5 minutes, the absorbance at 405 nm was continuously measured with a 96-well microplate reader (SpectraMAX250, Molecular Devices), and the increase in absorbance was used as an index of FXa activity. In order to evaluate the FXa inhibitory activity of the test compound, the concentration (IC ₅₀ value) at which the test compound inhibits the FXa activity by 50% relative to the control group was analyzed using analysis software (GraphPad Prism, GraphPad Software, Inc.). Calculated. The results are shown below.

Experimental Example 2: Antithrombotic action <Antithrombotic action in rat venous thrombus model>
A 7-week-old male Wistar rat (Charles River Japan) was used as a venous thrombus model test animal. The combination caused a thrombus in the descending vena cava. The test compound was dissolved or suspended in a 0.1% Nikkol HCO-60 (Nikko Chemicals) aqueous solution and orally administered (10 ml / kg) using an oral stomach tube. In the control group, only 0.1% Nikkol HCO-60 aqueous solution was administered in the same manner instead of the test compound. After administration of the test compound, thrombus formation was started from the time when the blood concentration of the test compound reached the peak, and the thrombus formed after 15 minutes was taken out, and its dry weight was weighed. The antithrombotic action was calculated by the following formula.
Thrombus weight reduction rate (%) = {1−thrombus weight of test compound group / thrombus weight of control group} × 100
It was also calculated using the analysis software ED ₅₀ values as the dose reducing the thrombus weight 50% (GraphPad Prism, GraphPad Software , Inc.). The results are shown below.

Preparation Example 1
N- (5-chloropyridin-2-yl) -5-methoxy-2-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) benzamide

参考例４で得られたトランス−４−（３−オキソモルホリン−４−イル）シクロヘキサンカルボン酸１２０ｍｇをクロロホルム３ｍｌに溶解し、１M塩化チオニル−クロロホルム溶液５４０μlおよびＮ，Ｎ−ジメチルホルムアミド１滴を加え、室温にて７時間攪拌した。反応液に２−アミノ−Ｎ−（５−クロロピリジン−２−イル）−５−メトキシベンズアミド１１１ｍｇおよびピリジン１ｍｌを加え、室温にて一晩攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を注ぎ、クロロホルムで抽出した。有機層を減圧下濃縮後、得られた残渣をＮＨ−シリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１に続き、酢酸エチル）にて精製し、表題化合物１５８ｍｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：４８７／４８９［Ｍ＋Ｈ］^＋。

120 mg of trans-4- (3-oxomorpholin-4-yl) cyclohexanecarboxylic acid obtained in Reference Example 4 was dissolved in 3 ml of chloroform, and 540 μl of 1M thionyl chloride-chloroform solution and one drop of N, N-dimethylformamide were added. And stirred at room temperature for 7 hours. To the reaction solution were added 2-amino-N- (5-chloropyridin-2-yl) -5-methoxybenzamide (111 mg) and pyridine (1 ml), and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1, followed by ethyl acetate) to obtain 158 mg of the title compound. . APCI-MS M / Z: 487/489 [M + H] ^< +>.

Preparation Example 2
4-{[(5-chloropyridin-2-yl) amino] carbonyl} -3-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) t-butyl benzoate

（１）４−（ｔ−ブトキシカルボニル）−２−ニトロ安息香酸１．０ｇをテトラヒドロフラン５０ｍｌに溶解し、２８％ナトリウムメトキシド−メタノール溶液０．７２ｇを加えた。トルエンを注ぎ減圧濃縮後、得られた残渣をクロロホルム５０ｍｌに懸濁し、オキサリルクロリド４８９μｌおよびＮ，Ｎ−ジメチルホルムアミドを２滴加え、室温にて３時間攪拌した。反応液を減圧下濃縮し、得られた残渣にクロロホルム２０ｍｌを注ぎ懸濁液とした。５−クロロ−２−アミノピリジン４８０ｍｇおよびピリジン４５３μｌをクロロホルム３０ｍｌに溶解後氷冷し、上記で調製した懸濁液を滴下した。反応液を室温にて８時間攪拌後、減圧下濃縮した。残渣を酢酸エチルにて希釈した後、１０％硫酸水素カリウム水溶液、飽和炭酸水素ナトリウム水溶液および飽和食塩水で順次洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝４／１）にて精製し、４−｛［（５−クロロピリジン−２−イル）アミノ］カルボニル｝−３−ニトロ安息香酸ｔ−ブチル８０３ｍｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：３７８［Ｍ＋Ｈ］^＋。

(1) 1.0 g of 4- (t-butoxycarbonyl) -2-nitrobenzoic acid was dissolved in 50 ml of tetrahydrofuran, and 0.72 g of 28% sodium methoxide-methanol solution was added. After toluene was poured and concentrated under reduced pressure, the resulting residue was suspended in 50 ml of chloroform, 489 μl of oxalyl chloride and 2 drops of N, N-dimethylformamide were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and 20 ml of chloroform was poured into the resulting residue to prepare a suspension. 480 mg of 5-chloro-2-aminopyridine and 453 μl of pyridine were dissolved in 30 ml of chloroform and then ice-cooled, and the suspension prepared above was added dropwise. The reaction solution was stirred at room temperature for 8 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4/1) to give 4-{[(5-chloropyridin-2-yl) amino] carbonyl} -3- 803 mg of t-butyl nitrobenzoate was obtained. APCI-MS M / Z: 378 [M + H] ^< +>.

(2) Dissolve 3.2 g of 4-{[(5-chloropyridin-2-yl) amino] carbonyl} -3-nitrobenzoate obtained in Preparation Example 2 (1) in 50 ml of tetrahydrofuran; Raney nickel was added, and the mixture was stirred overnight at room temperature under a pressurized (3 atm) hydrogen atmosphere. The insoluble material was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform / ethyl acetate = 20/1) to give 3-amino-4-{[(5-chloropyridin-2-yl) amino] carbonyl} benzoic acid t- 2.3 g of butyl was obtained. APCI-MS M / Z: 348 [M + H] ^< +>.

(3) 278 mg of 3-amino-4-{[(5-chloropyridin-2-yl) amino] carbonyl} benzoate obtained in Preparation Example 2 (2) was prepared in the same manner as in Preparation Example 1. Treatment gave 190 mg of the title compound. APCI-MS M / Z: 557/559 [M + H] ^< +>.

Preparation Example 3
4-{[(5-chloropyridin-2-yl) amino] carbonyl} -3-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) benzoic acid

調製例２で得られた４−｛［（５−クロロピリジン−２−イル）アミノ］カルボニル｝−３−（｛［トランス−４−（３−オキソモルホリン−４−イル）シクロヘキシル］カルボニル｝アミノ）安息香酸ｔ−ブチル２９３ｍｇをクロロホルム１０ｍｌに溶解し、４規定塩化水素−ジオキサン溶液１０ｍｌを加え、室温にて３日間攪拌した。反応液にジイソプロピルエーテルを注ぎ析出する固体を濾取し、表題化合物２８０ｍｇを得た。ＥＳＩ−ＭＳ Ｍ／Ｚ：４９９／５０１［Ｍ−Ｈ］⁻。

4-{[(5-chloropyridin-2-yl) amino] carbonyl} -3-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino obtained in Preparation Example 2 ) 293 mg of t-butyl benzoate was dissolved in 10 ml of chloroform, 10 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was stirred at room temperature for 3 days. Diisopropyl ether was poured into the reaction solution, and the precipitated solid was collected by filtration to obtain 280 mg of the title compound. ESI-MS M / Z: 499/501 [M−H] ⁻ .

Preparation Example 4
N ¹ - (5-chloropyridin-2-yl) -N ^4, N ⁴ - dimethyl-2 - ({[trans-4- (3-oxo-morpholin-4-yl) cyclohexyl] carbonyl} amino) terephthalamide

調製例３で得られた４−｛［（５−クロロピリジン−２−イル）アミノ］カルボニル｝−３−（｛［トランス−４−（３−オキソモルホリン−４−イル）シクロヘキシル］カルボニル｝アミノ）安息香酸５０ｍｇをピリジン１ｍｌに溶解し、塩酸ジメチルアミン２０ｍｇ、１−ヒドロキシベンゾトリアゾール２７ｍｇおよび塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド４０ｍｇを加え、室温にて２０時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を注ぎ、クロロホルムで抽出した。有機層を減圧下濃縮後、得られた残渣をＮＨ−シリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１に続き、酢酸エチル）にて精製し、表題化合物２８ｍｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：５２８／５３０［Ｍ＋Ｈ］^＋。

4-{[(5-chloropyridin-2-yl) amino] carbonyl} -3-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino obtained in Preparation Example 3 ) 50 mg of benzoic acid was dissolved in 1 ml of pyridine, 20 mg of dimethylamine hydrochloride, 27 mg of 1-hydroxybenzotriazole and 40 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide were added, and the mixture was stirred at room temperature for 20 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1, followed by ethyl acetate) to obtain 28 mg of the title compound. . APCI-MS M / Z: 528/530 [M + H] ⁺ .

Preparation Example 5
N- (5-chloropyridin-2-yl) -2-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) -4- (trifluoromethyl) benzamide

（１）２−ニトロ−４−（トリフルオロメチル）安息香酸３．０ｇをクロロホルム２５ｍｌに懸濁し、オキサリルクロリド１．６７ｍｌおよびＮ，Ｎ−ジメチルホルムアミドを２滴加え、室温にて３時間攪拌した。反応液を減圧下濃縮し、得られた残渣にクロロホルム２０ｍｌを注ぎ懸濁液とした。５−クロロ−２−アミノピリジン１．５６ｇおよびピリジン１．５５ｍｌにクロロホルム３０ｍｌを加えた後氷冷し、上記で調製した溶液を滴下した。反応液を室温にて８時間攪拌後、減圧下濃縮した。残渣を酢酸エチルにて希釈した後、１０％硫酸水素カリウム水溶液、飽和炭酸水素ナトリウム水溶液および飽和食塩水で順次洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をｎ−ヘキサンに懸濁後、濾取、乾燥し、Ｎ−（５−クロロピリジン−２−イル）−２−ニトロ−４−（トリフルオロメチル）ベンズアミド４．７３ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：３４６／３４８［Ｍ＋Ｈ］^＋。

(1) 3.0 g of 2-nitro-4- (trifluoromethyl) benzoic acid was suspended in 25 ml of chloroform, 1.67 ml of oxalyl chloride and 2 drops of N, N-dimethylformamide were added, and the mixture was stirred at room temperature for 3 hours. . The reaction solution was concentrated under reduced pressure, and 20 ml of chloroform was poured into the resulting residue to prepare a suspension. 30 ml of chloroform was added to 1.56 g of 5-chloro-2-aminopyridine and 1.55 ml of pyridine, and then ice-cooled, and the solution prepared above was added dropwise. The reaction solution was stirred at room temperature for 8 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was suspended in n-hexane, collected by filtration and dried to obtain 4.73 g of N- (5-chloropyridin-2-yl) -2-nitro-4- (trifluoromethyl) benzamide. . APCI-MS M / Z: 346/348 [M + H] ^< +>.

(2) Using 4.73 g of N- (5-chloropyridin-2-yl) -2-nitro-4- (trifluoromethyl) benzamide obtained in Preparation Example 5 (1) as in Preparation Example 2 (2) In this manner, 1.55 g of 2-amino-N- (5-chloropyridin-2-yl) -4- (trifluoromethyl) benzamide was obtained. APCI-MS M / Z: 316/318 [M + H] ^< +>.

(3) Treat 126 mg of 2-amino-N- (5-chloropyridin-2-yl) -4- (trifluoromethyl) benzamide obtained in Preparation Example 5 (2) in the same manner as in Preparation Example 1. This gave 183 mg of the title compound. APCI-MS M / Z: 525/527 [M + H] ⁺ .

Preparation Example 6
N- (5-chloropyridin-2-yl) -2-({[trans-4- (2-oxopyrrolidin-1-yl) cyclohexyl] carbonyl} amino) -4- (trifluoromethyl) benzamide

調製例５（２）で得られた２−アミノ−Ｎ−（５−クロロピリジン−２−イル）−４−（トリフルオロメチル）ベンズアミド７２ｍｇと参考例２で得られたトランス−４−（２−オキソピロリジン−１−イル）シクロヘキサンカルボン酸６３ｍｇを調製例１と同様の方法で処理することにより、表題化合物９５ｍｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：５０９／５１１［Ｍ＋Ｈ］^＋。

72 mg of 2-amino-N- (5-chloropyridin-2-yl) -4- (trifluoromethyl) benzamide obtained in Preparation Example 5 (2) and trans-4- (2 obtained in Reference Example 2 The title compound (95 mg) was obtained by treating 63 mg of (oxopyrrolidin-1-yl) cyclohexanecarboxylic acid in the same manner as in Preparation Example 1. APCI-MS M / Z: 509/511 [M + H] ⁺ .

Preparation Example 7
N- (5-chloropyridin-2-yl) -4,5-dimethoxy-2-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) benzamide

（１）Ｎ−（５−クロロピリジン−２−イル）−４，５−ジメトキシ−２−ニトロベンズアミド２．７３ｇを調製例２（２）と同様の方法で処理することにより、２−アミノ−Ｎ−（５−クロロピリジン−２−イル）−４，５−ジメトキシベンズアミド２．５３ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：３０８／３１０［Ｍ＋Ｈ］^＋。

(1) By treating 2.73 g of N- (5-chloropyridin-2-yl) -4,5-dimethoxy-2-nitrobenzamide in the same manner as in Preparation Example 2 (2), 2-amino- 2.53 g of N- (5-chloropyridin-2-yl) -4,5-dimethoxybenzamide was obtained. APCI-MS M / Z: 308/310 [M + H] ⁺ .

(2) By treating 123 mg of 2-amino-N- (5-chloropyridin-2-yl) -4,5-dimethoxybenzamide obtained in Preparation Example 7 (2) in the same manner as in Preparation Example 1. 163 mg of the title compound were obtained. APCI-MS M / Z: 517/519 [M + H] ^< +>.

Preparation Example 8-33
The corresponding amino compound and carboxylic acid compound were treated in the same manner as in Preparation Example 1 to obtain the compounds described in the following table.

Preparation Example 34
N- (5-chloropyridin-2-yl) -3-({[trans-4- (2-oxopyrrolidin-1-yl) cyclohexyl] carbonyl} amino) -2-naphthamide

（１）２Ｈ−ナフト［２，３−ｄ］［１，３］オキサジン−２，４（１Ｈ）−ジオン２１６ｍｇと２−アミノ−５−クロロピリジン２０２ｍｇのキシレン５ｍｌ懸濁液を１５０℃にて１３時間撹拌した後、４−ジメチルアミノピリジン１４．４ｍｇを加え、１５０℃にてさらに３時間撹拌した。反応液を減圧下濃縮後、得られた残渣を酢酸エチルに懸濁し、不溶物を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：ｎ−ヘキサン／酢酸エチル＝２／１)にて精製し、３−アミノ−Ｎ−（５−クロロピリジン−２−イル）−２−ナフトアミド２４ｍｇを得た。ＡＰＣＩ−ＭＳ ｍ／ｚ：２９８／３００［Ｍ＋Ｈ］^＋。

(1) A suspension of 2H-naphtho [2,3-d] [1,3] oxazine-2,4 (1H) -dione (216 mg) and 2-amino-5-chloropyridine (202 mg) in 5 ml of xylene at 150 ° C. After stirring for 13 hours, 14.4 mg of 4-dimethylaminopyridine was added, and the mixture was further stirred at 150 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was suspended in ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2/1) to give 3-amino-N- (5-chloropyridine-2- Yl) -2-naphthamide 24 mg was obtained. APCI-MS m / z: 298/300 [M + H] ⁺ .

(2) 40 mg of trans-4- (2-oxopyrrolidin-1-yl) cyclohexanecarboxylic acid obtained in Reference Example 2 was dissolved in 3 ml of chloroform, and 15 μl of thionyl chloride and 1 drop of N, N-dimethylformamide were added. Stir at room temperature for 15 hours. To the reaction solution, 31 mg of 3-amino-N- (5-chloropyridin-2-yl) -2-naphthamide obtained in Preparation Example 34 (1) and 1 ml of pyridine were added, and the mixture was stirred at room temperature for 12 hours. 43 mg of trans-4- (2-oxopyrrolidin-1-yl) cyclohexanecarboxylic acid, 42 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 56 mg of 4- (dimethylamino) pyridine were further added at room temperature. Stir for 12 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with chloroform, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by NH-silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 followed by 1/4) to obtain 36 mg of the title compound. . APCI-MS M / Z: 491/493 [M + H] ⁺ .

Preparation Example 35
N- (5-chloropyridin-2-yl) -3-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) pyridine-2-carboxamide

参考例４で得られたトランス−４−（３−オキソモルホリン−４−イル）シクロヘキサンカルボン酸１２０ｍｇをクロロホルム３ｍｌに溶解し、１M塩化チオニル−クロロホルム溶液５４０μlおよびＮ，Ｎ−ジメチルホルムアミド１滴を加え、室温にて７時間攪拌した。反応液に３−アミノ−Ｎ−（５−クロロピリジン−２−イル）ピリジン−２−カルボキサミド９９ｍｇおよびピリジン１ｍｌを加え、室温にて一晩攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を注ぎ、クロロホルムで抽出した。有機層を減圧下濃縮後、得られた残渣をＮＨ−シリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１に続き、酢酸エチル）にて精製し、表題化合物９４ｍｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：４５８／４６０［Ｍ＋Ｈ］^＋。

120 mg of trans-4- (3-oxomorpholin-4-yl) cyclohexanecarboxylic acid obtained in Reference Example 4 was dissolved in 3 ml of chloroform, and 540 μl of 1M thionyl chloride-chloroform solution and one drop of N, N-dimethylformamide were added. And stirred at room temperature for 7 hours. To the reaction mixture, 3-amino-N- (5-chloropyridin-2-yl) pyridine-2-carboxamide (99 mg) and pyridine (1 ml) were added, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1, followed by ethyl acetate) to obtain 94 mg of the title compound. . APCI-MS M / Z: 458/460 [M + H] ⁺ .

Preparation Examples 36-44
The corresponding amino compound and carboxylic acid compound were treated in the same manner as in Preparation Example 35 to obtain the compounds described in the following table.

Preparation Example 45
Methyl 3-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) thiophene-2-carboxylate

参考例４で得られたトランス−４−（３−オキソモルホリン−４−イル）シクロヘキサンカルボン酸１１９３ｍｇを塩化チオニル１０ｍｌに溶解し、室温にて１８時間攪拌した。反応液を減圧下濃縮し、残渣をトルエンで共沸後、クロロホルム７ｍｌに溶解した。３−アミノチオフェン−２−カルボン酸メチル７９ｍｇをピリジン３ｍｌに溶解後、氷冷下、上記で調製したクロロホルム溶液１ｍｌを滴下した。反応液を室温に戻し２１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を注ぎ、クロロホルムで抽出した。有機層を水および飽和食塩水で順次洗浄後、硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残渣をＮＨ−シリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１）にて精製し、表題化合物１８８ｍｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：３６７［Ｍ＋Ｈ］^＋。

1193 mg of trans-4- (3-oxomorpholin-4-yl) cyclohexanecarboxylic acid obtained in Reference Example 4 was dissolved in 10 ml of thionyl chloride and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene and then dissolved in 7 ml of chloroform. After dissolving 79 mg of methyl 3-aminothiophene-2-carboxylate in 3 ml of pyridine, 1 ml of the chloroform solution prepared above was added dropwise under ice cooling. The reaction solution was returned to room temperature and stirred for 21 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1) to obtain 188 mg of the title compound. APCI-MS M / Z: 367 [M + H] ^< +>.

Preparation Examples 46-68
The corresponding amino compound and carboxylic acid compound were treated in the same manner as in Preparation Example 45 to obtain the compounds described in the following table.

Preparation Example 69
N- (5-chloropyridin-2-yl) -3-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) thiophene-2-carboxamide

２−アミノ−５−クロロピリジン１７９ｍｇをクロロホルム５ｍｌに溶解し、氷冷下、０．９８Mトリメチルアルミニウム−ヘキサン溶液１．４２ｍｌを滴下した。反応液を室温にて０．５時間攪拌後、調製例４５で得られた３−（｛［トランス−４−（３−オキソモルホリン−４−イル）シクロヘキシル］カルボニル｝アミノ）チオフェン−２−カルボン酸メチル１７０ｍｇを加え、１８時間加熱還流した。放冷後、反応液に１０％塩酸４ｍｌを加えた後、クロロホルムで抽出した。有機層を水および飽和食塩水で順次洗浄後、硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残渣をＮＨ−シリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム）にて精製し、表題化合物１７２ｍｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：４６３／４６５［Ｍ＋Ｈ］^＋。

179 mg of 2-amino-5-chloropyridine was dissolved in 5 ml of chloroform, and 1.42 ml of 0.98 M trimethylaluminum-hexane solution was added dropwise under ice cooling. After stirring the reaction solution at room temperature for 0.5 hour, 3-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) thiophene-2-carboxylic acid obtained in Preparation Example 45 was obtained. 170 mg of methyl acid was added, and the mixture was heated to reflux for 18 hours. After allowing to cool, 4 ml of 10% hydrochloric acid was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (elution solvent: chloroform) to obtain 172 mg of the title compound. APCI-MS M / Z: 463/465 [M + H] ⁺ .

Preparation Example 70-92
The corresponding ester was treated in the same manner as in Preparation Example 69 to give the compound shown in the following table.

Preparation Examples 93-105
The corresponding amino compound and the carboxylic acid compound obtained in Reference Example 8-11 were treated in the same manner as in Preparation Example 1 to obtain the compounds described in the following table.

Reference example 1
Methyl trans-4-[(t-butoxycarbonyl) amino] cyclohexanecarboxylate

（１）−３０℃冷却下、メタノール１５００ｍｌに塩化チオニル２５４ｍｌを約１時間かけて滴下した。終了後、室温にて０．５時間攪拌した後、トランス−シクロヘキサン−１，４−ジカルボン酸５００．０ｇを加え室温にて１７時間攪拌した。反応液を減圧下濃縮し、残渣をクロロホルムで希釈後、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残渣をｎ−ヘキサンにて結晶化した後、濾取、乾燥し、トランス−シクロヘキサン−１，４−ジカルボン酸ジメチル５４５．０ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：２０１［Ｍ＋Ｈ］^＋。

(1) Under cooling at −30 ° C., 254 ml of thionyl chloride was added dropwise to 1500 ml of methanol over about 1 hour. After the completion, the mixture was stirred at room temperature for 0.5 hours, and then added with 500.0 g of trans-cyclohexane-1,4-dicarboxylic acid and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with chloroform, and then washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was crystallized from n-hexane, and then collected by filtration and dried to obtain 545.0 g of dimethyl trans-cyclohexane-1,4-dicarboxylate. APCI-MS M / Z: 201 [M + H] ^< +>.

(2) 150.0 g of dimethyl trans-cyclohexane-1,4-dicarboxylate obtained in Reference Example 1 (1) was dissolved in 1500 ml of tetrahydrofuran, and 149 g of 28% sodium methoxide-methanol solution and water 13 under ice cooling. .2 g of the mixed solution was added dropwise. The reaction solution was returned to room temperature and stirred for 3.5 hours, after which 1500 ml of n-hexane was poured, and the precipitate was collected by filtration. The obtained solid was added to a mixed solution of 50 ml of concentrated hydrochloric acid, 450 ml of water and 1000 ml of chloroform under ice-cooling, and stirred at room temperature for 20 minutes. The chloroform layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from n-hexane, then collected by filtration and dried to obtain 106.0 g of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid. ESI-MS / Z: 185 [M−H] ⁻ .

(3) After dissolving 100.0 g of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid obtained in Reference Example 1 (2) in 1000 ml of t-butanol, 155 g of diphenylphosphoric acid azide and 78.6 ml of triethylamine were added. The mixture was heated at about 60 ° C. for 1 hour and further heated to reflux for 17 hours. After allowing to cool, ice water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 250 ml of methanol, 750 ml of water was added, and the mixture was stirred under ice-cooling. After 0.5 hour, the precipitate was collected by filtration, washed successively with 1000 ml of water-methanol (3: 1) and n-hexane and then dried to obtain 117.0 g of the title compound. APCI-MS M / Z: 275 [M + H] ^< +>.

Reference example 2
Trans-4- (2-Oxopyrrolidin-1-yl) cyclohexanecarboxylic acid

（１）参考例１で得られたトランス−４−［（ｔ−ブトキシカルボニル）アミノ］シクロヘキサンカルボン酸メチル２３４．０ｇをジオキサン５００ｍｌに溶解し、４規定塩化水素−ジオキサン５００ｍｌを加え、室温にて１９時間攪拌した。反応液を減圧下濃縮し、得られた残渣をジエチルエーテルに懸濁後、析出物を濾取し、トランス−４−アミノシクロヘキサンカルボン酸メチル・塩酸塩１２１．９ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：１５８［Ｍ＋Ｈ］^＋。

(1) 234.0 g of methyl trans-4-[(t-butoxycarbonyl) amino] cyclohexanecarboxylate obtained in Reference Example 1 was dissolved in 500 ml of dioxane, 500 ml of 4N hydrogen chloride-dioxane was added, and at room temperature. Stir for 19 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was suspended in diethyl ether, and the precipitate was collected by filtration to obtain 121.9 g of trans-4-aminocyclohexanecarboxylate methyl hydrochloride. APCI-MS M / Z: 158 [M + H] ^< +>.

(2) 45.31 g of methyl trans-4-aminocyclohexanecarboxylate / hydrochloride obtained in Reference Example 2 (1) was suspended in 1000 ml of dichloromethane, and 31.5 ml of 4-chlorobutyryl chloride was added under ice cooling. Subsequently, a solution of 81.5 ml of triethylamine in 80 ml of dichloromethane was added dropwise. The reaction solution was returned to room temperature and stirred for 3 hours, and then the reaction solution was concentrated under reduced pressure. Ethyl acetate and 5% hydrochloric acid were poured into the obtained residue, and the organic layer was separated and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The extract was dried over sodium sulfate and treated with activated carbon, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended in diisopropyl ether, and the precipitate was collected by filtration and dried to obtain 38.81 g of methyl trans-4-[(4-chlorobutanoyl) amino] cyclohexanecarboxylate. APCI-MS M / Z: 262/264 [M + H] ^< +>.

(3) 9.60 g of 60% oily sodium hydride was suspended in 500 ml of N, N-dimethylacetamide, and trans-4-[(4-chlorobutanoyl) obtained in Reference Example 2 (2) under ice cooling. 52.32 g of methyl amino] cyclohexanecarboxylate was added in portions. The reaction solution was returned to room temperature, stirred for 24 hours, poured into a reaction solution with ice-cooled saturated ammonium chloride aqueous solution and ice water, and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and the residue was suspended in n-hexane-diisopropyl ether. The crystals were collected by filtration and dried to obtain 39.20 g of methyl trans-4- (2-oxopyrrolidin-1-yl) cyclohexanecarboxylate. APCI-MS M / Z: 226 [M + H] ^< +>.

(4) 39.15 g of methyl trans-4- (2-oxopyrrolidin-1-yl) cyclohexanecarboxylate obtained in Reference Example 2 (3) was dissolved in 400 ml of methanol, and 60 ml of 2N aqueous sodium hydroxide solution was added. And stirred at room temperature for 3 hours. Under ice cooling, 10% hydrochloric acid was poured to adjust the reaction solution to pH 1-2, saturated with sodium chloride, and extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was suspended in a small amount of ethyl acetate, poured into diisopropyl ether, and the crystals were collected by filtration. After washing several times with diisopropyl ether and drying, 35.94 g of the title compound was obtained. ESI-MS M / Z: 210 [M−H] ⁻ .

Reference example 3
Trans-4- [acetyl (methyl) amino] cyclohexanecarboxylic acid

（１）参考例１で得られたトランス−４−［（ｔ−ブトキシカルボニル）アミノ］シクロヘキサンカルボン酸メチル３０．００ｇをＮ，Ｎ−ジメチルホルムアミド１５０ｍｌに溶解し、氷冷下、６０％油性水素化ナトリウム５．６０ｇを加えた。同冷却下、０．５時間攪拌した後、ヨウ化メチル１４．５ｍｌおよびメタノール０．１５ｍｌを順次加え、反応液を室温に戻し４時間攪拌した。氷冷下、反応液に飽和塩化アンモニウム水溶液および氷水を注ぎ、酢酸エチルで抽出した。有機層を水および飽和食塩水で順次洗浄後、硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１０／１に続き、７／１）にて精製し、トランス−４−［（ｔ−ブトキシカルボニル）（メチル）アミノ］シクロヘキサンカルボン酸メチル２６．３３ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：２７２［Ｍ＋Ｈ］^＋。

(1) 30.00 g of methyl trans-4-[(t-butoxycarbonyl) amino] cyclohexanecarboxylate obtained in Reference Example 1 was dissolved in 150 ml of N, N-dimethylformamide, and 60% oily hydrogen was cooled on ice. 5.60 g of sodium chloride was added. After stirring for 0.5 hour under the same cooling, 14.5 ml of methyl iodide and 0.15 ml of methanol were sequentially added, and the reaction solution was returned to room temperature and stirred for 4 hours. Under ice-cooling, a saturated aqueous ammonium chloride solution and ice water were poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10/1 followed by 7/1), and trans-4-[(t-butoxycarbonyl) (methyl) amino There were obtained 26.33 g of methyl cyclohexanecarboxylate. APCI-MS M / Z: 272 [M + H] ^< +>.

(2) 26.32 g of methyl trans-4-[(t-butoxycarbonyl) (methyl) amino] cyclohexanecarboxylate obtained in Reference Example 3 (1) was dissolved in 100 ml of dioxane, and 4N hydrogen chloride-dioxane solution was obtained. 100 ml was added. After stirring the reaction solution at room temperature for 4 hours, 500 ml of diisopropyl ether was poured. The precipitate was collected by filtration, washed with diisopropyl ether and dried to obtain 19.01 g of methyl trans-4- (methylamino) cyclohexanecarboxylate / hydrochloride. APCI-MS M / Z: 172 [M + H] ^< +>.

(3) 18.93 g of methyl trans-4- (methylamino) cyclohexanecarboxylate / hydrochloride obtained in Reference Example 3 (2) was suspended in 400 ml of dichloromethane, and 8.42 ml of acetyl chloride was added under ice cooling. Subsequently, a solution of 38.1 ml of triethylamine in 40 ml of dichloromethane was added dropwise. The reaction solution was returned to room temperature and stirred for 2 hours, and then 5% hydrochloric acid was poured into the reaction solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (elution solvent: ethyl acetate) to obtain 19.05 g of methyl trans-4- [acetyl (methyl) amino] cyclohexanecarboxylate. APCI-MS M / Z: 214 [M + H] ^< +>.

(4) Dissolve 19.00 g of methyl trans-4- [acetyl (methyl) amino] cyclohexanecarboxylate obtained in Reference Example 3 (3) in 200 ml of methanol, add 60 ml of 2N aqueous sodium hydroxide solution, and bring it to room temperature. And stirred for 3 hours. Under ice cooling, 10% hydrochloric acid was poured to adjust the reaction solution to pH 1-2, saturated with sodium chloride, and extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was suspended in a small amount of ethyl acetate, poured into diisopropyl ether, and the crystals were collected by filtration. After washing several times with diisopropyl ether and drying, 16.31 g of the title compound was obtained. ESI-MS M / Z: 198 [MH] ⁻ .

Reference example 4
Trans-4- (3-Oxomorpholin-4-yl) cyclohexanecarboxylic acid

（１）６０％油性水素化ナトリウム６．８０ｇをＮ，Ｎ−ジメチルアセトアミド８０ｍｌに懸濁し、氷冷下、２−（ベンジルオキシ）エタノール１２．９ｇのＮ，Ｎ−ジメチルアセトアミド５０ｍｌ溶液を１０分間かけて滴下した。室温で１５分間撹拌した後、反応液を氷冷し、クロロ酢酸８．１３ｇを少しずつ加え、室温で１１時間撹拌した。反応液を減圧濃縮して得られた残渣に、炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで洗浄した。水層を濃塩酸で酸性にした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥、溶媒を減圧下留去して［２−（ベンジルオキシ）エトキシ］酢酸１８．２４ｇを得た。ＥＳＩ−ＭＳ Ｍ／Ｚ：２０９［Ｍ−Ｈ］⁻。

(1) 6.80 g of 60% oily sodium hydride was suspended in 80 ml of N, N-dimethylacetamide, and under ice cooling, a solution of 12.9 g of 2- (benzyloxy) ethanol in 50 ml of N, N-dimethylacetamide was added for 10 minutes. It was dripped over. After stirring at room temperature for 15 minutes, the reaction solution was ice-cooled, 8.13 g of chloroacetic acid was added little by little, and the mixture was stirred at room temperature for 11 hours. To the residue obtained by concentrating the reaction solution under reduced pressure, an aqueous sodium hydrogen carbonate solution was added and washed with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 18.24 g of [2- (benzyloxy) ethoxy] acetic acid. ESI-MS M / Z: 209 [M−H] ⁻ .

(2) 6.51 g of [2- (benzyloxy) ethoxy] acetic acid obtained in Reference Example 4 (1), methyl trans-4-aminocyclohexanecarboxylate / hydrochloride 5 obtained in Reference Example 2 (1) .27 g and 5.06 g of 1-hydroxybenzotriazole were dissolved in 100 ml of N, N-dimethylformamide, and 7.10 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and triethylamine were added under ice cooling. 50 ml was sequentially added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1 followed by ethyl acetate), and trans-4-({[2- (2-benzyloxy) ethoxy] acetyl } Amino) 8.24 g of methyl cyclohexanecarboxylate was obtained. APCI-MS M / Z: 350 [M + H] ^< +>.

(3) Dissolve 5.09 g of trans-4-({[2- (2-benzyloxy) ethoxy] acetyl} amino) cyclohexanecarboxylate obtained in Reference Example 4 (2) in 150 ml of acetic acid, 5% Palladium-carbon (1.01 g) was added, and the mixture was stirred at room temperature for 2.4 hours under a normal pressure hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain trans-4-{[(2-hydroxyethoxy) acetyl] amino}. 3.32 g of methyl cyclohexanecarboxylate was obtained. APCI-MS M / Z: 260 [M + H] ^< +>.

(4) 1.37 g of methyl trans-4-{[(2-hydroxyethoxy) acetyl] amino} cyclohexanecarboxylate obtained in Reference Example 4 (3) was dissolved in 15 ml of chloroform, and 890 μl of triethylamine was added under ice cooling. It was. Subsequently, 450 μl of methanesulfonyl chloride was added dropwise at the same temperature. The reaction mixture was stirred under ice-cooling for 3 hours, diluted with water and extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure to give trans-4-[({2-[(methylsulfonyl) oxy] ethoxy} acetyl) amino] cyclohexanecarboxylic acid. 1.83 g of methyl were obtained. APCI-MS M / Z: 338 [M + H] ^< +>.

(5) 1.08 g of methyl trans-4-[({2-[(methylsulfonyl) oxy] ethoxy} acetyl) amino] cyclohexanecarboxylate obtained in Reference Example 4 (4) was added to 15 ml of N, N-dimethylacetamide. Then, 135% of 60% oily sodium hydride was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Water and excess sodium chloride were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1 followed by ethyl acetate), and methyl trans-4- (3-oxomorpholin-4-yl) cyclohexanecarboxylate. 715 mg was obtained. APCI-MS M / Z: 242 [M + H] ^< +>.

(6) By treating 500 mg of methyl trans-4- (3-oxomorpholin-4-yl) cyclohexanecarboxylate obtained in Reference Example 4 (5) in the same manner as in Reference Example 2 (4), the title 322 mg of compound was obtained. ESI-MS M / Z: 226 [M−H] ⁻ .

Reference Example 5
Trans-4- (2-Oxo-1,3-oxazolidine-3-yl) cyclohexanecarboxylic acid

（１）参考例２（１）で得られたトランス−４−アミノシクロヘキサンカルボン酸メチル・塩酸塩５．００ｇをクロロホルム６０ｍｌに溶解し、氷冷下、トリエチルアミン１１ｍｌを加え、続いてクロロギ酸２−クロロエチル３．３ｍｌのクロロホルム１０ｍｌ溶液を滴下した。室温にて２．５時間撹拌後、反応液に５％塩酸を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残渣をクロロホルム−ジイソプロピルエーテルに懸濁し、析出物を濾取後、乾燥して、トランス−４−{［（２−クロロエトキシ）カルボニル］アミノ}シクロヘキサンカルボン酸メチル５．１１ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：２６４／２６６［Ｍ＋Ｈ］^＋。

(1) 5.00 g of methyl trans-4-aminocyclohexanecarboxylate / hydrochloride obtained in Reference Example 2 (1) was dissolved in 60 ml of chloroform, and 11 ml of triethylamine was added under ice cooling, followed by 2-chloroformate 2- A solution of 3.3 ml of chloroethyl in 10 ml of chloroform was added dropwise. After stirring at room temperature for 2.5 hours, 5% hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was suspended in chloroform-diisopropyl ether, and the precipitate was collected by filtration and dried to obtain 5.11 g of methyl trans-4-{[(2-chloroethoxy) carbonyl] amino} cyclohexanecarboxylate. . APCI-MS M / Z: 264/266 [M + H] ^< +>.

(2) 3.70 g of methyl trans-4-{[(2-chloroethoxy) carbonyl] amino} cyclohexanecarboxylate obtained in Reference Example 5 (1) was dissolved in 50 ml of N, N-dimethylacetamide and ice-cooled. Then, 630 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature for 16.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1, followed by ethyl acetate), and trans-4- (2-oxo-1 , 3-Oxazolidin-3-yl) cyclohexanecarboxylate 1.83 g. APCI-MS M / Z: 228 [M + H] ^< +>.

(3) A method similar to that in Reference Example 2 (4), using 1.84 g of methyl trans-4- (2-oxo-1,3-oxazolidine-3-yl) cyclohexanecarboxylate obtained in Reference Example 5 (2) To give 1.75 g of the title compound. ESI-MS M / Z: 212 [MH] ^- .

Reference Example 6
5- (2-Oxopyrrolidin-1-yl) pentanoic acid

（１）５−アミノ吉草酸７．３５ｇをメタノール５０ｍｌに溶解し、氷冷下、塩化チオニル４．９ｍｌを滴下後、反応液を室温に戻し１７時間攪拌した。反応液を減圧下濃縮し、得られた残渣をジエチルエーテルに懸濁後、析出物を濾取し、５−アミノ吉草酸メチル・塩酸塩９．９３ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：１３２［Ｍ＋Ｈ］^＋。

(1) 7.35 g of 5-aminovaleric acid was dissolved in 50 ml of methanol, 4.9 ml of thionyl chloride was added dropwise under ice cooling, and then the reaction solution was returned to room temperature and stirred for 17 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in diethyl ether. The precipitate was collected by filtration to obtain 9.93 g of methyl 5-aminovalerate / hydrochloride. APCI-MS M / Z: 132 [M + H] ^< +>.

(2) 1.68 g of methyl 5-aminovalerate / hydrochloride obtained in Reference Example 6 (1) was suspended in 20 ml of chloroform, 2.54 g of triethylamine was added under ice cooling, and 4-chlorobutyryl was then added. 1.55 g of chloride was added dropwise. The reaction solution was returned to room temperature and stirred for 2 hours, and then ice water was poured into the reaction solution and extracted with chloroform. The organic layer was washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.34 g of methyl 5-[(4-chlorobutanoyl) amino] pentanoate. APCI-MS M / Z: 236/238 [M + H] ^< +>.

(3) 2.33 g of methyl 5-[(4-chlorobutanoyl) amino] pentanoate obtained in Reference Example 6 (2) was dissolved in 20 ml of N, N-dimethylacetamide, and 60% oily under ice cooling. Sodium hydride 0.47 g was added in small portions. The reaction solution was returned to room temperature and stirred for 20 hours, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: chloroform, followed by chloroform / ethyl acetate = 20/1) to give 2.15 g of methyl 5- (2-oxopyrrolidin-1-yl) pentanoate. Obtained. APCI-MS M / Z: 200 [M + H] ⁺ .

(4) 1.00 g of methyl 5- (2-oxopyrrolidin-1-yl) pentanoate obtained in Reference Example 6 (3) was dissolved in 20 ml of methanol, and 2.5 ml of 4N aqueous sodium hydroxide solution was added. Thereafter, the reaction solution was returned to room temperature and stirred for 18 hours. The reaction mixture was washed with diethyl ether, 5.0 ml of 2N hydrochloric acid was added, and the mixture was concentrated under reduced pressure. The obtained residue was extracted with chloroform and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.90 g of the title compound. ESI-MS M / Z: 184 [M−H] ⁻ .

Reference Example 7
5- (3-Oxomorpholin-4-yl) pentanoic acid

（１）参考例６（１）で得られた５−アミノ吉草酸メチル・塩酸塩３．３５ｇ、参考例４（１）で得られた［２−（ベンジルオキシ）エトキシ］酢酸４．６３ｇ、および１−ヒドロキシベンゾトリアゾール３．７８ｇをＮ，Ｎ−ジメチルホルムアミド８０ｍｌに溶解し、氷冷下、塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド５．３７ｇおよびトリエチルアミン３．３５ｍｌを順次加え、室温で２日間撹拌した。反応液を減圧濃縮して得られた残渣を氷水で希釈し、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液、水および飽和食塩水で順次洗浄後、硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１に続き、酢酸エチル）にて精製し、５−（{［２−（ベンジルオキシ）エトキシ］アセチル}アミノ）ペンタン酸メチル５．５６ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：３２４［Ｍ＋Ｈ］^＋。

(1) 3.35 g of methyl 5-aminovalerate / hydrochloride obtained in Reference Example 6 (1), 4.63 g of [2- (benzyloxy) ethoxy] acetic acid obtained in Reference Example 4 (1), And 1.78 g of 1-hydroxybenzotriazole were dissolved in 80 ml of N, N-dimethylformamide, and 5.37 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 3.35 ml of triethylamine were successively added under ice cooling. In addition, the mixture was stirred at room temperature for 2 days. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with ice water and extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1 followed by ethyl acetate), and 5-({[2- (benzyloxy) ethoxy] acetyl} amino) pentane. 5.56 g of methyl acid was obtained. APCI-MS M / Z: 324 [M + H] ^< +>.

(2) 5.54 g of methyl 5-({[2- (benzyloxy) ethoxy] acetyl} amino) pentanoate obtained in Reference Example 7 (1) was dissolved in 60 ml of tetrahydrofuran, and 20% palladium hydroxide-carbon was added. 0.5 g was added, and the mixture was stirred at room temperature for 4 hours under a normal pressure hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain 3.76 g of methyl 5-{[(2-hydroxyethoxy) acetyl] amino} pentanoate. APCI-MS M / Z: 234 [M + H] ^< +>.

(3) 1.17 g of methyl 5-{[(2-hydroxyethoxy) acetyl] amino} pentanoate obtained in Reference Example 7 (2) was dissolved in 15 ml of chloroform, and 0.84 ml of triethylamine was added under ice cooling. . Subsequently, 0.43 ml of methanesulfonyl chloride was added dropwise at the same temperature. The reaction solution was returned to room temperature and stirred for 1 hour, and then ice water was poured and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give methyl 5-[({2-[(methylsulfonyl) oxy] ethoxy} acetyl) amino] pentanoate. 51 g was obtained. APCI-MS M / Z: 312 [M + H] ^< +>.

(4) 1.48 g of methyl 5-[({2-[(methylsulfonyl) oxy] ethoxy} acetyl) amino] pentanoate obtained in Reference Example 7 (3) was dissolved in 22 ml of N, N-dimethylacetamide. Under ice cooling, 0.20 g of 60% oily sodium hydride was added and stirred at room temperature for 18 hours. Ice water was poured into the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1 followed by ethyl acetate), and methyl 3- (3-oxomorpholin-4-yl) pentanoate (0.93 g). Got. APCI-MS M / Z: 216 [M + H] ^< +>.

(5) After dissolving 500 mg of methyl 5- (3-oxomorpholin-4-yl) pentanoate obtained in Reference Example 7 (4) in 10 ml of methanol and adding 2 ml of aqueous sodium hydroxide (0.40 g) The reaction solution was returned to room temperature and stirred for 17 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 2N hydrochloric acid, and concentrated under reduced pressure. The obtained residue was extracted with chloroform, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.35 g). ESI-MS M / Z: 200 [M−H] ⁻ .

Reference Example 8
Trans-4-[(Dimethylamino) carbonyl] cyclohexanecarboxylic acid

（１）参考例１（２）で得られたトランス−４−（メトキシカルボニル）シクロヘキサンカルボン酸２０．０ｇをクロロホルム２００ｍｌに溶解し、氷冷下、塩酸ジメチルアミン１０．５ｇ、塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド２４．７ｇ、およびトリエチルアミン２６．０ｇを加え、室温にて１７時間攪拌した。反応液に氷水を注ぎ、クロロホルムで抽出した。有機層を１０％塩酸、飽和炭酸水素ナトリウム水溶液、および飽和食塩水にて順次洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルムに続き、クロロホルム／メタノール＝２０／１）にて精製し、トランス−４−［（ジメチルアミノ）カルボニル］シクロヘキサンカルボン酸メチル２０．１ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：２１４［Ｍ＋Ｈ］^＋。

(1) 20.0 g of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid obtained in Reference Example 1 (2) was dissolved in 200 ml of chloroform, and 10.5 g of dimethylamine hydrochloride and 1-ethyl hydrochloride of hydrochloric acid were cooled with ice. 3- (3-Dimethylaminopropyl) carbodiimide (24.7 g) and triethylamine (26.0 g) were added, and the mixture was stirred at room temperature for 17 hours. Ice water was poured into the reaction solution and extracted with chloroform. The organic layer was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After concentrating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent: chloroform followed by chloroform / methanol = 20/1), and trans-4-[(dimethylamino) carbonyl] cyclohexanecarboxylic acid was obtained. 20.1 g of methyl acid was obtained. APCI-MS M / Z: 214 [M + H] ^< +>.

(2) 20.0 g of methyl trans-4-[(dimethylamino) carbonyl] cyclohexanecarboxylate obtained in Reference Example 8 (1) was dissolved in 100 ml of methanol, and 7.50 g of sodium hydroxide was dissolved in 40 ml of water. The solution was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ice water and washed with diethyl ether. The obtained aqueous layer was acidified with 10% hydrochloric acid and extracted twice with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was suspended in n-hexane and collected by filtration to obtain 15.7 g of the title compound. ESI-MS M / Z: 198 [MH] ⁻ .

Reference Example 9
Trans-4- (Pyrrolidin-1-ylcarbonyl) cyclohexanecarboxylic acid

（１）参考例１（２）で得られたトランス−４−（メトキシカルボニル）シクロヘキサンカルボン酸２０．０ｇをクロロホルム２００ｍｌに溶解し、氷冷下、ピロリジン９．２ｇ、塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド２４．７ｇ、およびトリエチルアミン１３．６ｇを加え、室温にて１７時間攪拌した。反応液に氷水を注ぎ、クロロホルムで抽出した。有機層を１０％塩酸、飽和炭酸水素ナトリウム水溶液、および飽和食塩水にて順次洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルムに続き、クロロホルム／メタノール＝２０／１）にて精製し、トランス−４−（ピロリジン−１−イルカルボニル）シクロヘキサンカルボン酸メチル１１．８ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：２４０［Ｍ＋Ｈ］^＋。

(1) 20.0 g of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid obtained in Reference Example 1 (2) was dissolved in 200 ml of chloroform, and 9.2 g of pyrrolidine and 1-ethyl-3-hydrochloride under ice cooling. 24.7 g of (3-dimethylaminopropyl) carbodiimide and 13.6 g of triethylamine were added, and the mixture was stirred at room temperature for 17 hours. Ice water was poured into the reaction solution and extracted with chloroform. The organic layer was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After concentrating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform followed by chloroform / methanol = 20/1), and trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexane. 11.8 g of methyl carboxylate was obtained. APCI-MS M / Z: 240 [M + H] ^< +>.

(2) 11.7 g of methyl trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexanecarboxylate obtained in Reference Example 9 (1) was dissolved in 50 ml of methanol, and 3.95 g of sodium hydroxide was dissolved in 20 ml of water. The solution was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ice water and washed with diethyl ether. The obtained aqueous layer was acidified with 10% hydrochloric acid and extracted twice with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was suspended in n-hexane and collected by filtration to obtain 10.1 g of the title compound. ESI-MS M / Z: 224 [M−H] ⁻ .

Reference Example 10
Trans-4- (morpholin-4-ylcarbonyl) cyclohexanecarboxylic acid

（１）参考例１（２）で得られたトランス−４−（メトキシカルボニル）シクロヘキサンカルボン酸８００ｍｇをクロロホルム３０ｍｌに溶解し、氷冷下、モルホリン５６０ｍｇ、塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド１．２４ｇ、およびトリエチルアミン６５０ｍｇを加え、室温にて１９時間攪拌した。反応液に氷水を注ぎ、クロロホルムで抽出した。有機層を１０％塩酸、飽和炭酸水素ナトリウム水溶液、および飽和食塩水にて順次洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルムに続き、クロロホルム／メタノール＝３０／１）にて精製し、トランス−４−（モルホリン−４−イルカルボニル）シクロヘキサンカルボン酸メチル８９７ｍｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：２５６［Ｍ＋Ｈ］^＋。

(1) 800 mg of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid obtained in Reference Example 1 (2) was dissolved in 30 ml of chloroform, 560 mg of morpholine, 1-ethyl-3- (3-dimethyl hydrochloride) under ice cooling. Aminopropyl) carbodiimide (1.24 g) and triethylamine (650 mg) were added, and the mixture was stirred at room temperature for 19 hours. Ice water was poured into the reaction solution and extracted with chloroform. The organic layer was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After concentrating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent: chloroform followed by chloroform / methanol = 30/1), and trans-4- (morpholin-4-ylcarbonyl) cyclohexane. 897 mg of methyl carboxylate was obtained. APCI-MS M / Z: 256 [M + H] ⁺ .

(2) 860 mg of methyl trans-4- (morpholin-4-ylcarbonyl) cyclohexanecarboxylate obtained in Reference Example 10 (1) was dissolved in 40 ml of methanol, and 1.68 ml of 4N aqueous sodium hydroxide solution was added, For 18 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ice water, neutralized with 10% hydrochloric acid, and extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 638 mg of the title compound. ESI-MS M / Z: 240 [M−H] ⁻ .

Reference Example 11
Trans-4-{[[2- (Dimethylamino) ethyl] (methyl) amino] carbonyl} cyclohexanecarboxylic acid

（１）参考例１（２）で得られたトランス−４−（メトキシカルボニル）シクロヘキサンカルボン酸８．８４ｇをクロロホルム１００ｍｌに溶解し、氷冷下、１−ヒドロキシベンゾトリアゾール７．１４ｇ、塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド１０．００ｇ、およびＮ，Ｎ，Ｎ'−トリメチルエチレンジアミン５．３３ｇを加え、室温にて４時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を注ぎ、クロロホルムで抽出した。有機層を飽和食塩水にて洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール／２８％アンモニア水＝２００／１０／１）にて精製し、トランス−４−｛［［２−（ジメチルアミノ）エチル］（メチル）アミノ］カルボニル｝シクロヘキサンカルボン酸メチル１１．９８ｇを得た。ＡＰＣＩ−ＭＳ Ｍ／Ｚ：２７１［Ｍ＋Ｈ］^＋。

(1) Dissolve 8.84 g of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid obtained in Reference Example 1 (2) in 100 ml of chloroform, and under ice cooling, 7.14 g of 1-hydroxybenzotriazole, 1-hydrochloric acid 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide (10.00 g) and N, N, N′-trimethylethylenediamine (5.33 g) were added, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. After concentrating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol / 28% aqueous ammonia = 200/10/1) to obtain trans-4-{[[2- ( 11.98 g of methyl (dimethylamino) ethyl] (methyl) amino] carbonyl} cyclohexanecarboxylate was obtained. APCI-MS M / Z: 271 [M + H] ^< +>.

(2) Dissolve 6.32 g of trans-4-{[[2- (dimethylamino) ethyl] (methyl) amino] carbonyl} cyclohexanecarboxylate obtained in Reference Example 11 (1) in 20 ml of methanol. 25 ml of a normal sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 3 hours. After adding 25 ml of 1N hydrochloric acid to the reaction solution, the reaction solution was concentrated under reduced pressure. The residue was lyophilized to give 6.71 g of the title compound as a crude product containing equimolar sodium chloride. APCI-MS M / Z: 257 [M + H] ^< +>.

A pharmaceutical composition containing compound [1] or a pharmacologically acceptable salt thereof as an active ingredient is low toxic and safe, and has an excellent FXa inhibitory action, thus preventing diseases caused by thrombus or embolism. Or it is useful as a therapeutic agent.

Claims (4)

General formula [1]:

(In the formula, X represents a group represented by the formula: —N═ or the formula: —CH═. Y ¹ and Y ² are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, A halogen atom-substituted lower alkyl group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylcarbamoyl group and a phenyl group, and R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. ² represents a group represented by the formula: —CO—R ²¹ —R ²² , R ²¹ represents a lower alkylene group or a cycloalkanediyl group, and R ²² represents

Indicates. R ²³ and R ²⁴ are the same or different and represent a lower alkyl group or an amino lower alkyl group which may be substituted with a lower alkyl group, or R ²³ and R ²⁴ are adjacent to each other at the end. : Forms a nitrogen-containing saturated heterocyclic group which may be substituted together with the group represented by —N—C (═O) —. R ²⁵ and R ²⁶ are the same or different and each represents a lower alkyl group or an amino lower alkyl group which may be substituted with a lower alkyl group, or R ²⁵ and R ²⁶ are bonded to each other at the end and adjacent nitrogen atoms. A nitrogen-containing saturated heterocyclic group which may be substituted with an atom is formed. Ring A represents an aromatic hydrocarbon ring, a monocyclic heteroaromatic ring or a condensed thiophene ring. And a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising a pharmacologically acceptable carrier. General formula [1]:

(In the formula, X represents a group represented by the formula: —N═ or the formula: —CH═. Y ¹ and Y ² are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, A halogen atom-substituted lower alkyl group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylcarbamoyl group and a phenyl group, and R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. ² represents a group represented by the formula: —CO—R ²¹ —R ²² , R ²¹ represents a lower alkylene group or a cycloalkanediyl group, and R ²² represents

Indicates. R ²³ and R ²⁴ are the same or different and represent a lower alkyl group or an amino lower alkyl group which may be substituted with a lower alkyl group, or R ²³ and R ²⁴ are adjacent to each other at the end. : Forms a nitrogen-containing saturated heterocyclic group which may be substituted together with the group represented by —N—C (═O) —. R ²⁵ and R ²⁶ are the same or different and each represents a lower alkyl group or an amino lower alkyl group which may be substituted with a lower alkyl group, or R ²⁵ and R ²⁶ are bonded to each other at the end and adjacent nitrogen atoms. A nitrogen-containing saturated heterocyclic group which may be substituted with an atom is formed. Ring A represents an aromatic hydrocarbon ring, a monocyclic heteroaromatic ring or a condensed thiophene ring. An activated blood coagulation factor X inhibitor containing as an active ingredient an amide type carboxamide derivative represented by formula (I) or a pharmacologically acceptable salt thereof. The activated blood coagulation factor X inhibitor according to claim 2, which is a prophylactic or therapeutic agent for diseases caused by thrombi and emboli. N- (5-chloropyridin-2-yl) -5-methoxy-2-({[trans-4- (3-oxomorpholin-4-yl) cyclohexyl] carbonyl} amino) benzamide or a pharmaceutically acceptable salt thereof An activated blood coagulation factor X inhibitor comprising a salt that can be obtained as an active ingredient.