JP4665769B2 - Method for producing acylaminothiazole derivative - Google Patents

Description

  The present invention relates to a method for producing a novel 2-acylaminothiazole derivative or a salt thereof useful as a pharmaceutical, particularly a therapeutic agent for thrombocytopenia.

Platelets are anucleated blood cells that play a major role in physiological hemostasis and pathological thrombus formation. In vivo, platelets are continuously produced from megakaryocytes, which are progenitor cells. Platelet production is derived from pluripotent stem cells like other blood cells, and pluripotent stem cells become megakaryocyte progenitor cells, and then become megakaryoblasts, pre-megakaryocytes, and megakaryocytes. In the process of maturation of megakaryocytes, immature megakaryocytes are polyploidized by only DNA synthesis without cell division. Thereafter, cytoplasm maturation begins, a platelet separation membrane is formed, the cytoplasm is ruptured, and platelets are released.
On the other hand, platelet reduction due to various hematopoietic disorders in aplastic anemia, myelodysplastic syndrome or malignant tumor chemotherapy, radiotherapy, etc. causes serious symptoms such as bleeding tendency. Attempts have been made to develop various techniques for increasing platelets for the purpose. Currently, platelet transfusion is the most effective means of treating thrombocytopenia, but it is not a situation where a sufficient amount of platelets is being supplied, and thrombocytopenia is sufficiently prevented because of the short life of the transferred platelets. It is difficult to improve. Furthermore, platelet transfusion has problems such as viral infection, production of alloantibodies, and Graft Versus Host Disease (GVHD). For this reason, development of a drug that alleviates the state of suppression of hematopoietic function caused by various symptoms or treatment and promotes recovery of the platelet count is expected.

  Under such circumstances, thrombopoietin (TPO), a c-Mpl ligand, is a major factor involved in the differentiation into megakaryocyte cells, and it stimulates the differentiation and proliferation of megakaryocyte cells to produce platelets. (Kaushansky K. et. Al., Nature, 369, 568-571, 1994: Non-Patent Document 1 and Lok S. et. Al., Nature, 369, 565-568, 1994). : Non-patent document 2). TPO has already been clinically tested as a platelet-increasing agent, and its usefulness and tolerability in humans is being confirmed. However, in a clinical trial of PEG-rHuMGDF, which is a type of TPO (the 163rd amino acid from the N-terminus of TPO is modified with polyethylene glycol), neutralizing antibodies were confirmed (Li J. et. Al., Blood, 98, 3241-3248, 2001: Non-patent document 3 and Basser RL et. Al., Blood, 99, 2599-2602, 2002: Non-patent document 4), there is concern about the immunogenicity of TPO. . Moreover, since TPO is a protein, it is degraded in the digestive tract and is not practical as an orally administered drug. For the same reason, it is considered that low molecular weight peptides are not practical as orally administered drugs. Under such circumstances, development of a non-peptide c-Mpl ligand that is less immunogenic and can be administered orally for the purpose of treating thrombocytopenia is underway.

  Examples of such compounds include benzodiazepine derivatives (Patent Document 1), acylhydrazone derivatives (Patent Document 2), diazonaphthalene derivatives (Patent Document 3), pyrrolocarbazole derivatives (Patent Document 4), and pyrrolophenanthridine derivatives (Patents). Document 5) and pyrrolophthalimide derivatives (Patent Document 6) are known.

（式中の記号は、該公報参照）
該公報では、X¹として置換されていてもよいチアゾール、Y¹として-NHCO-を含む化合物についての記載がある。しかし、本発明の製造法の目的物においては、該公報におけるチアゾリル基のごときA¹基を有する置換基で置換されることはない。しかも、該公報においては、チアゾール5位がN-置換メチルアミノメチル基で置換されている化合物については、実施例その他による具体的開示は一切ない。 In addition, International Publication WO 01/07423 (Patent Document 7) describes that a compound represented by the following general formula (VII) has a platelet-increasing action.

(Refer to this publication for symbols in the formula)
This publication describes a thiazole which may be substituted as X ¹ and a compound containing —NHCO— as Y ¹ . However, the object of the production method of the present invention is not substituted with a substituent having an A ¹ group such as the thiazolyl group in the publication. In addition, this publication does not disclose any specific disclosure of the compound in which the 5-position of thiazole is substituted with an N-substituted methylaminomethyl group.

（式中の記号は、該公報参照）
該公報では、X¹として置換されていてもよいチアゾール、Y¹として-NHCO-を含む化合物についての記載がある。しかし、本発明の製造法の目的物においては、該公報におけるW¹基を有する置換基で置換されることはない。しかも、該公報においては、チアゾール5位がN-置換メチルアミノメチル基で置換されている化合物については、実施例その他による具体的開示は一切ない。 In addition, International Publication WO 01/53267 (Patent Document 8) describes that a compound represented by the following general formula (VIII) has a platelet-increasing action.

(Refer to this publication for symbols in the formula)
This publication describes a thiazole which may be substituted as X ¹ and a compound containing —NHCO— as Y ¹ . However, the object of the production method of the present invention is not substituted with the substituent having the W ¹ group in the publication. In addition, this publication does not disclose any specific disclosure of the compound in which the 5-position of thiazole is substituted with an N-substituted methylaminomethyl group.

（式中の記号は、該公報参照）
該公報では、2-アシルアミノチアゾールの5位に窒素原子が直接置換した化合物についての記載がある。しかし、本発明の製造法の目的物のごとくチアゾール5位がN-置換メチルアミノメチル基で置換されている化合物については記載も示唆もない。 In addition, International Publication WO 02/62775 (Patent Document 9) describes that a compound represented by the following general formula (IX) has a platelet-increasing action.

(Refer to this publication for symbols in the formula)
The publication describes a compound in which a nitrogen atom is directly substituted at the 5-position of 2-acylaminothiazole. However, there is no description or suggestion of a compound in which the thiazole 5-position is substituted with an N-substituted methylaminomethyl group as in the object of the production method of the present invention.

（式中の記号は、該公報参照）
該公報では、2-アシルアミノチアゾールの5位に窒素原子が直接置換した化合物についての記載がある。しかし、本発明の製造法の目的物のごとくチアゾール5位がN-置換メチルアミノメチル基で置換されている化合物については記載も示唆もない。
上記文献には、いずれも本発明の製造法の目的物である化合物の記載はなく、従って、本発明の製造法については記載も示唆もされていない。
上記のような状況下、血小板減少症治療を目的とした、免疫原性が少なく経口投与可能な非ペプチド性c-Mplリガンドの開発が切望されている。
特開平11-152276号公報 国際公開第99/11262号パンフレット 国際公開第00/35446号パンフレット 国際公開第98/09967号パンフレット 特開平10-212289号公報 特開2000-44562公報 国際公開第01/07423号パンフレット 国際公開第01/53267号パンフレット 国際公開第02/62775号パンフレット 国際公開第03/062233号パンフレット ネイチャー（Nature）、1994年、第369号、p.568-571 ネイチャー（Nature）、1994年、第369号、p.565-568 ブラッド（Blood）、2001年、第98巻、p.3241-3248 ブラッド（Blood）、2002年、第99巻、p.2599-2602 In addition, International Publication No. WO 03/062233 (Patent Document 10) describes that a compound represented by the following general formula (X) has a platelet-increasing action.

(Refer to this publication for symbols in the formula)
The publication describes a compound in which a nitrogen atom is directly substituted at the 5-position of 2-acylaminothiazole. However, there is no description or suggestion of a compound in which the thiazole 5-position is substituted with an N-substituted methylaminomethyl group as in the object of the production method of the present invention.
None of the above documents describes a compound that is the object of the production method of the present invention, and therefore neither describes nor suggests the production method of the present invention.
Under the circumstances as described above, development of a non-peptide c-Mpl ligand that is less immunogenic and can be administered orally for the purpose of treating thrombocytopenia is eagerly desired.
JP-A-11-152276 WO99 / 11262 pamphlet International Publication No. 00/35446 Pamphlet International Publication No. 98/09967 Pamphlet Japanese Patent Laid-Open No. 10-212289 JP 2000-44562 A International Publication No. 01/07423 Pamphlet International Publication No. 01/53267 Pamphlet International Publication No. 02/62775 Pamphlet International Publication No. 03/062233 Pamphlet Nature, 1994, No. 369, p.568-571 Nature, 1994, 369, p.565-568 Blood, 2001, Vol. 98, p.3241-3248 Blood, 2002, Vol. 99, p.2599-2602

  The present inventors have found a novel 2-acylaminothiazole derivative having an excellent platelet-increasing action, and have earnestly studied its production method to complete the present invention.

［式中の記号は、以下の意味を示す。
-R¹：低級アルキル、若しくはシクロアルキル。
-A=：-N=、若しくは-CH=。
-X：ハロゲン。
-Y-：（ａ）-A=が-N=である場合、-NR³-。（ｂ）-A=が-CH=である場合、-O-。
-R²：-OH、アミノ、及び低級アルキルスルホニルアミノからなる群より選択される基で置換されている低級アルキル。
-R³：-H、若しくは低級アルキル。
あるいは、R²とR³は隣接する窒素原子と一体となって、カルボキシル、及び-CO₂-低級アルキルからなる群より選択される基で置換されたピペリジン-1-イル；若しくはオキソ基で置換されたピペラジン-1-イル；を示してもよい。］
で示される2-アシルアミノチアゾール誘導体又はその製薬学的に許容される塩の製造法。
なお、製造法群Pは、以下の（１）乃至（５）の製造法からなる群である。
（１）-A=が-N=であり、従って-Y-が-NR³-であり、R²とR³が隣接する窒素原子と一体となって、-CO₂-低級アルキルで置換されたピペリジン-1-イルである場合：
式（１Ａ）で示されるピペリジンエステル誘導体

［式中の記号は、以下の意味を示す。
-X：ハロゲン。
-R^1A：低級アルキル。］
に対してN-R¹-N-メチルアミノメチル基を導入することを含む、式（Ｉ）で示される2-アシルアミノチアゾール誘導体又はその製薬学的に許容される塩の製造法。
（２）-A=が-N=であり、従って-Y-が-NR³-であり、R²とR³が隣接する窒素原子と一体となって、カルボキシルで置換されたピペリジン-1-イルである場合：
式（２Ａ）で示されるピペリジンエステル誘導体

［式中の記号は、以下の意味を示す。
-R¹：低級アルキル、若しくはシクロアルキル。
-X：ハロゲン。
-R^2A：低級アルキル。］
を加水分解反応に付すことを含む、式（Ｉ）で示される2-アシルアミノチアゾール誘導体又はその製薬学的に許容される塩の製造法。
（３）-A=が-N=であり、従って-Y-が-NR³-であり、-R²が-OH、アミノ、及び低級アルキルスルホニルアミノからなる群より選択される基で置換されている低級アルキルであり、-R³が-H、若しくは低級アルキルである場合；又は、-A=が-N=であり、従って-Y-が-NR³-であり、R²とR³が隣接する窒素原子と一体となって、オキソ基で置換されたピペラジン-1-イルである場合：
式（３Ａ）で示されるピリジン誘導体

［式中の記号は、以下の意味を示す。
-R¹：低級アルキル、若しくはシクロアルキル。
-X：ハロゲン。
-W：脱離基。］
に対して、式（３Ｂ）で示されるアミン誘導体

［式中の記号は、以下の意味を示す。
-R^3B2：-OH、アミノ、及び低級アルキルスルホニルアミノからなる群より選択される基で置換されている低級アルキル。なお、当該低級アルキルの置換基が-OH若しくはアミノである場合、それらの基は保護されていてもよい。
-R^3B3：-H、若しくは低級アルキル。
あるいは、R^3B2とR^3B3は隣接する窒素原子と一体となって、オキソ基で置換されたピペラジン-1-イルを示してもよい。］
を付加し、R^3B2が保護された-OH若しくは保護されたアミノである場合には、さらにその保護基を脱離させることを含む、式（Ｉ）で示される2-アシルアミノチアゾール誘導体又はその製薬学的に許容される塩の製造法。
（４）-A=が-N=であり、従って-Y-が-NR³-であり、-R²が低級アルキルスルホニルアミノで置換されている低級アルキルであり、-R³が-H、若しくは低級アルキルである場合：
式（４Ａ）で示されるアミノピリジン誘導体

［式中の記号は、以下の意味を示す。
-R¹：低級アルキル、若しくはシクロアルキル。
-X：ハロゲン。
-R^4A：アミノで置換されている低級アルキル。
-R³：-H、若しくは低級アルキル。］
に対して、低級アルキルスルホニル化剤を作用させることを含む、式（Ｉ）で示される2-アシルアミノチアゾール誘導体又はその製薬学的に許容される塩の製造法。
（５）-A=が-CH=であり、従って-Y-が-O-である場合：
式（５Ａ）で示されるフェニルエーテル誘導体

［式中の記号は、以下の意味を示す。
-X：ハロゲン。
-R^5A：-OH、アミノ、及び低級アルキルスルホニルアミノからなる群より選択される基で置換されている低級アルキル。なお、当該低級アルキルの置換基が-OH若しくはアミノである場合、それらの基は保護されていてもよい。］
に対してN-R¹-N-メチルアミノメチル基を導入し、R^5Aが保護された-OH若しくは保護されたアミノである場合には、さらにその保護基を脱離させることを含む、式（Ｉ）で示される2-アシルアミノチアゾール誘導体又はその製薬学的に許容される塩の製造法。
（Ｂ）-A=が-N=であり、従って-Y-が-NR³-であり、R²とR³が隣接する窒素原子と一体となって、-CO₂-低級アルキルで置換されたピペリジン-1-イルである（Ａ）記載の式（Ｉ）の化合物の製造法であって、
式（１Ａ）で示されるピペリジンエステル誘導体

［式中の記号は、以下の意味を示す。
-X：ハロゲン。
-R^1A：低級アルキル。］
に対してN-R¹-N-メチルアミノメチル基を導入することを含む、（Ａ）に記載の製造法。
（Ｃ）-A=が-N=であり、従って-Y-が-NR³-であり、R²とR³が隣接する窒素原子と一体となって、カルボキシルで置換されたピペリジン-1-イルである（Ａ）記載の式（Ｉ）の化合物の製造法であって、
式（２Ａ）で示されるピペリジンエステル誘導体

［式中の記号は、以下の意味を示す。
-R¹：低級アルキル、若しくはシクロアルキル。
-X：ハロゲン。
-R^2A：低級アルキル。］
を加水分解反応に付すことを含む、（Ａ）に記載の製造法。
（Ｄ）-A=が-N=であり、従って-Y-が-NR³-であり、-R²が-OH、アミノ、及び低級アルキルスルホニルアミノからなる群より選択される基で置換されている低級アルキルであり、-R³が-H、若しくは低級アルキルである（Ａ）記載の式（Ｉ）の化合物；又は、-A=が-N=であり、従って-Y-が-NR³-であり、R²とR³が隣接する窒素原子と一体となって、オキソ基で置換されたピペラジン-1-イルである（Ａ）記載の式（Ｉ）の化合物の製造法であって、
式（３Ａ）で示されるピリジン誘導体

［式中の記号は、以下の意味を示す。
-R¹：低級アルキル、若しくはシクロアルキル。
-X：ハロゲン。
-W：脱離基。］
に対して、式（３Ｂ）で示されるアミン誘導体

［式中の記号は、以下の意味を示す。
-R^3B2：-OH、アミノ、及び低級アルキルスルホニルアミノからなる群より選択される基で置換されている低級アルキル。なお、当該低級アルキルの置換基が-OH若しくはアミノである場合、それらの基は保護されていてもよい。
-R^3B3：-H、若しくは低級アルキル。
あるいは、R^3B2とR^3B3は隣接する窒素原子と一体となって、オキソ基で置換されたピペラジン-1-イルを示してもよい。］
を付加し、R^3B2が保護された-OH若しくは保護されたアミノである場合には、さらにその保護基を脱離させることを含む、（Ａ）に記載の製造法。
（Ｅ）-A=が-N=であり、従って-Y-が-NR³-であり、-R²が低級アルキルスルホニルアミノで置換されている低級アルキルであり、-R³が-H、若しくは低級アルキルである（Ａ）記載の式（Ｉ）の化合物の製造法であって、
式（４Ａ）で示されるアミノピリジン誘導体

［式中の記号は、以下の意味を示す。
-R¹：低級アルキル、若しくはシクロアルキル。
-X：ハロゲン。
-R^4A：アミノで置換されている低級アルキル。
-R³：-H、若しくは低級アルキル。］
に対して、低級アルキルスルホニル化剤を作用させることを含む、（Ａ）に記載の製造法。
（Ｆ）-A=が-CH=であり、従って-Y-が-O-である（Ａ）記載の式（Ｉ）の化合物の製造法であって、
式（５Ａ）で示されるフェニルエーテル誘導体

［式中の記号は、以下の意味を示す。
-X：ハロゲン。
-R^5A：-OH、アミノ、及び低級アルキルスルホニルアミノからなる群より選択される基で置換されている低級アルキル。なお、当該低級アルキルの置換基が-OH若しくはアミノである場合、それらの基は保護されていてもよい。］
に対してN-R¹-N-メチルアミノメチル基を導入し、R^5Aが保護された-OH若しくは保護されたアミノである場合には、さらにその保護基を脱離させることを含む、（Ａ）に記載の製造法。 That is, according to the present invention, the following (A) to (F) are provided.
(A) Formula (I), which is one production method selected from production method group P

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-A =: -N = or -CH =.
-X: Halogen.
-Y - :( a) if -A = is -N =, -NR ³ -. (B) -O- when -A = is -CH =.
-R ^2: -OH, amino, and lower alkyl substituted by a group selected from the group consisting of lower alkylsulfonylamino.
-R ³ : -H or lower alkyl.
Alternatively, R ² and R ³ together with the adjacent nitrogen atom are substituted with a group selected from the group consisting of carboxyl and —CO ₂ -lower alkyl; or substituted with an oxo group Piperazin-1-yl; ]
A process for producing a 2-acylaminothiazole derivative represented by the formula: or a pharmaceutically acceptable salt thereof.
The production method group P is a group consisting of the following production methods (1) to (5).
(1) -A = is -N =, therefore -Y- is -NR ^3- , R ² and R ³ are combined with the adjacent nitrogen atom and substituted with -CO ₂ -lower alkyl. If piperidin-1-yl is:
Piperidine ester derivatives represented by the formula (1A)

[The symbols in the formula have the following meanings.
-X: Halogen.
-R ^1A : Lower alkyl. ]
A method for producing a 2-acylaminothiazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, which comprises introducing an NR ¹ -N-methylaminomethyl group into the compound.
(2) Piperidine-1-, wherein -A = is -N =, and therefore -Y- is -NR ^3- , R ² and R ³ are combined with the adjacent nitrogen atom and substituted with carboxyl If it is:
Piperidine ester derivatives represented by the formula (2A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-R ^2A: lower alkyl. ]
A method for producing a 2-acylaminothiazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, which comprises subjecting to hydrolysis.
(3) -A = is -N =, therefore -Y- is -NR ^3- , and -R ² is substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino Or -R ³ is -H or lower alkyl; or -A = is -N = and therefore -Y- is -NR ^3- , R ² and R ³ Is piperazin-1-yl substituted with an oxo group together with an adjacent nitrogen atom:
A pyridine derivative represented by the formula (3A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-W: leaving group. ]
An amine derivative represented by the formula (3B)

[The symbols in the formula have the following meanings.
-R ^3B2 : lower alkyl substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino. In addition, when the lower alkyl substituent is —OH or amino, these groups may be protected.
-R ^3B3 : -H or lower alkyl.
Alternatively, R ^3B2 and R ^3B3 may be combined with an adjacent nitrogen atom to represent piperazin-1-yl substituted with an oxo group. ]
In the case where R ^3B2 is protected —OH or protected amino, the 2-acylaminothiazole derivative represented by the formula (I) or further comprising A method for producing a pharmaceutically acceptable salt.
(4) -A = is -N =, therefore -Y- is -NR ^3- , -R ² is lower alkyl substituted with lower alkylsulfonylamino, -R ³ is -H, Or if it is lower alkyl:
Aminopyridine derivative represented by the formula (4A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-R ^4A : Lower alkyl substituted with amino.
-R ³ : -H or lower alkyl. ]
A method for producing a 2-acylaminothiazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, which comprises reacting a lower alkylsulfonylating agent.
(5) When -A = is -CH = and therefore -Y- is -O-:
Phenyl ether derivative represented by the formula (5A)

[The symbols in the formula have the following meanings.
-X: Halogen.
-R ^5A : lower alkyl substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino. In addition, when the lower alkyl substituent is —OH or amino, these groups may be protected. ]
Incorporating an NR ¹ -N-methylaminomethyl group into the group, and when R ^5A is protected —OH or protected amino, further comprises removing the protecting group. ) A 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.
(B) -A = is -N =, therefore -Y- is -NR ^3- , R ² and R ³ are combined with the adjacent nitrogen atom and substituted with -CO ₂ -lower alkyl. A process for preparing a compound of formula (I) as described in (A) which is piperidin-1-yl,
Piperidine ester derivatives represented by the formula (1A)

[The symbols in the formula have the following meanings.
-X: Halogen.
-R ^1A : Lower alkyl. ]
The production method according to (A), comprising introducing an NR ¹ -N-methylaminomethyl group into
(C) -A = is -N =, therefore -Y- is -NR ^3- , and R ² and R ³ are combined with the adjacent nitrogen atom to form a carboxyl-substituted piperidine-1- A process for the preparation of a compound of formula (I) as described in (A),
Piperidine ester derivatives represented by the formula (2A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-R ^2A: lower alkyl. ]
The manufacturing method as described in (A) including attaching | subjecting to a hydrolysis reaction.
(D) -A = is -N =, therefore -Y- is -NR ^3- , and -R ² is substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino. Or a compound of formula (I) as described in (A) wherein -R ³ is -H or lower alkyl; or -A = is -N = and therefore -Y- is -NR ³ - and there in together with the nitrogen atom to which R ² and R ³ are adjacent, a piperazine-1-yl substituted with oxo group (a) preparation of compounds of formula (I) according And
A pyridine derivative represented by the formula (3A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-W: leaving group. ]
An amine derivative represented by the formula (3B)

[The symbols in the formula have the following meanings.
-R ^3B2 : lower alkyl substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino. In addition, when the lower alkyl substituent is —OH or amino, these groups may be protected.
-R ^3B3 : -H or lower alkyl.
Alternatively, R ^3B2 and R ^3B3 together with the adjacent nitrogen atom may represent piperazin-1-yl substituted with an oxo group. ]
When R ^3B2 is protected —OH or protected amino, the production method according to (A), further comprising removing the protecting group.
(E) -A = is -N =, therefore -Y- is -NR ^3- , -R ² is lower alkyl substituted with lower alkylsulfonylamino, -R ³ is -H, Or a process for the preparation of a compound of formula (I) as described in (A) which is lower alkyl,
Aminopyridine derivative represented by the formula (4A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-R ^4A : Lower alkyl substituted with amino.
-R ³ : -H or lower alkyl. ]
The method according to (A), which comprises allowing a lower alkylsulfonylating agent to act on
(F) A process for preparing a compound of formula (I) as described in (A), wherein -A = is -CH = and therefore -Y- is -O-,
Phenyl ether derivative represented by the formula (5A)

[The symbols in the formula have the following meanings.
-X: Halogen.
-R ^5A : lower alkyl substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino. In addition, when the lower alkyl substituent is —OH or amino, these groups may be protected. ]
NR ¹ -N-methylaminomethyl group is introduced into the group, and when R ^5A is protected —OH or protected amino, further removing the protecting group, (A) The production method described in 1.

In addition, -R ¹ in the target compound of the production method of the present invention represented by the formula (I) is preferably normal butyl or cyclobutyl.
Further, -X in the target compound of the production method of the present invention represented by the formula (I) is preferably chloro or fluoro, and chloro is particularly preferable.
Further, when -YR ² represents piperidin-1-yl substituted with a group selected from the group consisting of carboxyl and -CO ₂ -lower alkyl, carboxyl substituted with piperidin-1-yl, or- The CO ₂ -lower alkyl is preferably substituted at the 4-position of the piperidine.

INDUSTRIAL APPLICABILITY The present invention is useful for providing a production method for advantageously producing a novel 2-acylaminothiazole derivative or a salt thereof having an excellent platelet-increasing action.
Moreover, the 2-acylaminothiazole derivative or a salt thereof, which is produced by the production method of the present invention and is a target product of the production method of the present invention, is a compound having an excellent platelet-increasing action. Therefore, these compounds are associated with aplastic anemia, thrombocytopenia in myelodysplastic syndrome, chemotherapy for malignant tumors, thrombocytopenia due to radiation therapy, idiopathic thrombocytopenic purpura, thrombocytopenia in liver disease, due to HIV It is useful for the treatment and / or prevention of various thrombocytopenia such as thrombocytopenia, and when there is a possibility of thrombocytopenia caused by chemotherapy or radiation therapy, it should be administered before administration It can also be left.
The pharmacological action of the compound according to the object of the production method of the present invention was confirmed by the following test.

(I) Human c-mpl-Ba / F3 cell proliferation test
In a 96-well microplate, 2 x 10 ⁵ cells / ml human c-mpl-Ba / F3 cells (Ba / F3 cell stable transformants in which human c-mpl is forcibly expressed) The cells were cultured at 37 ° C. in RPMI 1640 medium (100 μl / well) containing 10% fetal calf serum. Twenty-four hours after the start of culture, 10 μl / well of WST-1 / 1-methoxy PMS (cell measurement kit, Dojin) was added. Immediately after addition and 2 hours later, the absorbance of A450 / A650 was measured with a microplate reader (Model 3350: Bio-Rad), and the increase in absorbance at 2 hours was defined as the proliferation activity of each test compound. The results are shown in Table 1.

The symbols in the table have the following meanings.
pot: Test compound concentration that promotes cell growth 30% of the maximum cell growth activity of compound A (compound A and rhTPO in rhTPO)
Efficacy: The maximum cell growth activity value of the test compound when the maximum cell growth activity value of compound A (rhTPO in compound A and rhTPO) is 100%.
Compound A represents the compound of Example 9 of Patent Document 10 described above.

表中、比較化合物１とは、上述の特許文献７の化合物番号A-1の化合物であり；比較化合物２とは、上述の特許文献８の化合物番号A-14の化合物であり；比較化合物３とは、上述の特許文献８の化合物番号J-14の化合物であり；比較化合物４とは、上述の特許文献９の実施例２の化合物である。比較化合物１〜４、及び化合物Aの構造を以下に示す。

上記の結果より、本発明の製造法の目的物である化合物がヒトc-Mplを介したBa/F3細胞増殖作用を有することが確認された。

In the table, Comparative Compound 1 is the compound of Compound No. A-1 in Patent Document 7 described above; Comparative Compound 2 is the compound of Compound No. A-14 in Patent Document 8 described above; Comparative Compound 3 Is the compound of Compound No. J-14 of Patent Document 8 described above; Comparative Compound 4 is the compound of Example 2 of Patent Document 9 described above. The structures of Comparative Compounds 1 to 4 and Compound A are shown below.

From the above results, it was confirmed that the compound which is the object of the production method of the present invention has a Ba / F3 cell proliferation action via human c-Mpl.

(Ii) Measurement test for promoting megakaryocyte colony formation Human CD34 ⁺ cells containing abundant human hematopoietic progenitor cells were assayed in a 2 well chamber slide using MegaCult ^™ -C (StemCell Technologies) in the presence of a test substance. Cultured at 37 ° C. for one day. After dehydration and fixation according to the attached instructions, staining was performed with an anti-glycoprotein IIb / IIIa antibody that specifically binds to megakaryocyte cells. A group of 3 or more stained megakaryocyte cells was regarded as one colony, and the number of colonies per well was measured with a microscope. The EC ₃₀ value of each test compound was calculated from the dose curve.

As a result, the EC ₃₀ value of the target compound of the production method of the present invention was 20 nM for the compound of Example 2, 34 nM for the compound of Example 10, and 36 nM for the compound of Example 12. It was confirmed that the compound which is the object of the production method of the present invention has an excellent megakaryocyte colony formation promoting action.

(Iii) Mouse Oral Administration Test Test compounds 3 mg / kg or 10 mg / kg (100 mg / kg in Comparative Compounds 1 to 3) dissolved or suspended in 0.5% methylcellulose aqueous solution are orally administered to male ICR mice. Administered. Two hours after administration, 1/10 volume 3.8% sodium citrate was collected as an anticoagulant from the inferior vena cava. Plasma obtained by centrifugation at 12,000 rpm for 3 minutes was heated at 56 ° C. for 30 minutes and added to the human c-mpl-Ba / F3 cell proliferation test system described in (i) at final concentrations of 0.3% and 1% Or it added so that it might become 3% plasma (10% in the comparison compounds 1-3), and the cell growth activity was measured. The cell proliferation activity (%) of each plasma was determined when the maximum cell proliferation activity of each test compound was taken as 100%. The results are shown in Table 2.

表中の比較化合物１〜３は、上記表１における比較化合物１〜３とそれぞれ同一の化合物である。

Comparative compounds 1 to 3 in the table are the same compounds as comparative compounds 1 to 3 in Table 1, respectively.

  From the above results, it was confirmed that the compound which is the object of the production method of the present invention has oral activity in mice. In particular, the comparative compound showed almost no oral activity even in the “100 mg / kg-10% dilution conditions”, but the compound which is the object of the production method of the present invention “has a lower dose. It was very surprising that it was found to have good oral activity even at `` 3 mg / kg or 10 mg / kg-higher than 3% dilution '' condition, which is the thiazole 5-position. This is considered to be achieved by introducing an N-substituted methylaminomethyl group as a substituent. In Comparative Compound 2 and Comparative Compound 3, the cell proliferation activity was 10% or less even at a lower dose (10 mg / kg p.o.).

  In addition, it was confirmed that, after the transplantation of human hematopoietic stem cells, platelet-increasing activity was observed by administering a compound which is the object of the production method of the present invention to mice in which human platelet production was observed.

The compound that is the object of the production method of the present invention will be further described as follows.
In the present specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
Accordingly, “lower alkyl” refers to C _1-6 alkyl, specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like. Preferred are C _1-3 alkyl methyl, ethyl, propyl and isopropyl.
“Cycloalkyl” means a C _3-8 carbocycle which may have a partially unsaturated bond, and specifically includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclobutenyl, Examples thereof include cyclohexenyl and cyclooctadienyl.
“Halogen” includes fluoro, chloro, bromo and iodo, preferably fluoro and chloro.
The “NR ¹ -N-methylaminomethyl group” means an aminomethyl group in which the amino group is substituted with a group represented by R ¹ and methyl.
The “leaving group” represented by —W in formula (3A) may be any group that functions as a leaving group in the substitution reaction with the amine derivative represented by formula (3B). And halogen such as fluoro and chloro; and sulfonyloxy groups such as methanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethanesulfonyloxy. Preferably, it is fluoro or chloro.
In -R ^3B2 and -R ^5A , "in the case of -OH or amino, these groups may be protected" means that the -OH or amino can be easily converted to -OH or amino. This means that it may be substituted, and examples of such a group that can be converted to —OH or amino include the following groups.
Groups convertible to —OH: lower alkylcarbonyloxy groups such as acetyloxy groups; benzoyloxy groups; benzyloxy groups; tri-lower alkylsilyloxy groups such as tert-butyldimethylsilyloxy groups; : Lower alkyloxycarbonyl group such as tert-butyloxycarbonylamino group; lower alkylsulfonylamino group such as methanesulfonylamino group; lower alkylcarbonylamino group such as acetylamino group; etc.

  Depending on the type of the substituent, the compound represented by the formula (I), which is an object of the production method of the present invention, may contain an asymmetric carbon atom, and optical isomers based on this may exist. The present invention encompasses all methods for producing a mixture of these optical isomers and isolated ones. In addition, the compound which is the object of the production method of the present invention may have a tautomer, but the present invention includes a production method of a mixture of these isomers or a mixture thereof. In addition, the present invention includes a method for producing a label, that is, a compound in which one or more atoms of a compound that is an object of the production method of the present invention are substituted with a radioactive isotope or a non-radioactive isotope.

  In addition, the compound that is the object of the production method of the present invention may form a salt and is included in the present invention as long as the salt is a pharmaceutically acceptable salt. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, metals such as sodium, potassium, calcium, magnesium Examples thereof include inorganic bases, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts, and the like. Furthermore, the present invention also includes a process for producing various hydrates, solvates and crystal polymorphs of the compound which is the object of the production process of the present invention and pharmaceutically acceptable salts thereof. The present invention also includes all methods for producing so-called prodrugs, which are metabolized in vivo and converted to the compound represented by the formula (I) or a salt thereof. Examples of the group that forms a prodrug in the compound that is the object of the production method of the present invention include the group described in Prog. Med. 5: 2157-2161 (1985), and Yodogawa Shoten 1990 published "Development of Pharmaceuticals". Vol. 7 Molecular Design The groups described in pages 163-198 are listed.

(Production method)
The production method of the present invention will be described in detail below. Depending on the type of functional group, it may be effective in terms of production technology to replace the functional group with a suitable protecting group at the raw material or intermediate stage, that is, a group that can be easily converted to the functional group. is there. Thereafter, the protecting group is removed as necessary to obtain the desired compound. Examples of such functional groups include a hydroxyl group, a carboxyl group, an amino group, and the like, and examples of protective groups thereof include, for example, “Protective Groups in Organic Synthesis (third edition)” by Greene and Wuts. Can be used as appropriate according to the reaction conditions.

［式中、R^1A、X、R¹は上述の意味を示し、AcOHは酢酸、Acはアセチルを意味する。］
（工程Ａ）
本工程は、R¹で置換されたメチルアミン誘導体を用いたマンニッヒ（Mannich）反応を用いて、化合物（１Ａ）のチアゾール５位にR¹で置換されたメチルアミノ基を導入し、本発明の製造法の目的物に係る化合物（Ｉ）を製造する工程である。Albertson, N. F.; J Am Chem Soc 1948, 70, 669.や、Bhargava, P. N.; Sharma, S. C.; Bull Chem Soc Jpn 1965, 38, 909.に記載された方法、あるいはそれに準じた方法を採用することができる。
（工程Ｂ、工程Ｃ）
本工程は、化合物（１Ａ）のチアゾール５位にアセトキシメチル基を導入して化合物（１Ａ−１）とした後、塩基性条件化、R¹で置換されたメチルアミン誘導体による求核置換反応を経て本発明の製造法の目的物に係る化合物（Ｉ）を製造する工程である。
工程Ｂのアセトキシメチル化は、化合物（１Ａ）に対し、酢酸溶媒下、ホルムアルデヒド水溶液若しくはパラホルムアルデヒドを作用させ、室温乃至加熱下、若しくは室温乃至還流下に行うことができる。なお、酢酸溶媒に代えて、ジクロロメタン、ジクロロエタン、クロロホルム等のハロゲン化炭化水素類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類；エーテル、テトラヒドロフラン（THF）等のエーテル類；等の反応に不活性な溶媒下、酢酸を加えて反応させることもできるが、その場合には反応性が低下する傾向がある。また、さらに無水酢酸を加えて反応を行うこともできる。
工程Ｃの求核置換反応は、化合物（１Ａ−１）に対し、ハロゲン化炭化水素類；芳香族炭化水素類；エーテル類；酢酸エチル（EtOAc）等のエステル類；アセトニトリル；N,N-ジメチルホルムアミド（DMF）；ジメチルスルホキシド（DMSO）等の反応に不活性な有機溶媒中、トリエチルアミン、ジイソプロピルエチルアミン等の有機塩基、及び／又は炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素ナトリウム等の無機塩基存在下、R¹で置換されたメチルアミン誘導体を作用させることにより行うことができる。なお、反応を加速させるために、ジメチルアミノピリジン等の触媒を加えてもよい。また、有機塩基及び／又は無機塩基に代えて、R¹で置換されたメチルアミン誘導体を過剰に用いてもよい。反応は用いる塩基によって異なるが、冷却乃至室温下、室温下乃至加熱下、室温下乃至還流下に行うことができる。
なお、本製造法の原料化合物である化合物（１Ａ）は、本願明細書実施例記載の方法のほか、それに準じた方法、当業者にとって自明である方法、又はそれらを組み合わせることにより、容易に製造することができる。 (First Production Method) -A = is -N =, therefore -Y- is -NR ^3- , R ² and R ³ are combined with the adjacent nitrogen atom, and -CO ₂ -lower alkyl is Process for the preparation of compounds of formula (I) which are substituted piperidin-1-yl

[Wherein R ^1A , X and R ¹ have the above-mentioned meanings, AcOH means acetic acid, and Ac means acetyl. ]
(Process A)
This process uses a Mannich (Mannich-) reaction with methylamine derivatives substituted by R ^1, introducing a methylamino group substituted by R ¹ thiazole 5-position of the compound (1A), of the present invention This is a step for producing compound (I) according to the object of the production method. The methods described in Albertson, NF; J Am Chem Soc 1948, 70, 669., Bhargava, PN; Sharma, SC; Bull Chem Soc Jpn 1965, 38, 909. it can.
(Process B, Process C)
In this step, an acetoxymethyl group is introduced into the 5-position of thiazole of compound (1A) to form compound (1A-1), and then basic conditioning and nucleophilic substitution with a methylamine derivative substituted with R ¹ are performed. This is a step for producing compound (I) according to the object of the production method of the present invention.
The acetoxymethylation in Step B can be carried out on compound (1A) by reacting an aqueous formaldehyde solution or paraformaldehyde in an acetic acid solvent and at room temperature to heating, or from room temperature to reflux. Instead of acetic acid solvents, halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ether and tetrahydrofuran (THF); The reaction can also be carried out by adding acetic acid under an active solvent, but in this case, the reactivity tends to decrease. Further, the reaction can be carried out by further adding acetic anhydride.
The nucleophilic substitution reaction in Step C is carried out by reacting compound (1A-1) with halogenated hydrocarbons; aromatic hydrocarbons; ethers; esters such as ethyl acetate (EtOAc); acetonitrile; N, N-dimethyl Formamide (DMF); in an organic solvent inert to the reaction such as dimethyl sulfoxide (DMSO), organic bases such as triethylamine and diisopropylethylamine, and / or inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate below it can be carried out by the action of methylamine derivative substituted with R ^1. In order to accelerate the reaction, a catalyst such as dimethylaminopyridine may be added. Further, instead of the organic base and / or the inorganic base, a methylamine derivative substituted with R ¹ may be used in excess. The reaction varies depending on the base used, but can be carried out under cooling to room temperature, from room temperature to heating, or from room temperature to reflux.
In addition, the compound (1A) which is a raw material compound of this production method can be easily produced by the method described in the Examples of the present application, a method according to the method, a method obvious to those skilled in the art, or a combination thereof. can do.

［式中の記号は上述の意味を示す。］
本製法は、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の無機塩基を、メタノール（MeOH）、エタノール（EtOH）、2-プロパノール等のアルコール類若しくは水、又はこれらの混合溶媒中、化合物（２Ａ）に作用させて加水分解反応に付すことにより、本発明の製造法の目的物に係る化合物（Ｉ）を製造する方法である。加水分解反応は、上述のProtective Groups in Organic Synthesisに記載の方法や、それらに準じた方法、又は当業者にとって自明である方法を用いることができる。
なお、本製造法の原料化合物である化合物（２Ａ）は、本願明細書実施例記載の方法のほか、それに準じた方法、当業者にとって自明である方法、又はそれらを組み合わせることにより、容易に製造することができる。また、第１製法で製造した本発明の製造法の目的物に係る化合物が、本製造法の原料化合物である化合物（２Ａ）として用いられることもある。 (Second Production Method) -A = is -N =, and therefore -Y- is -NR ^3- , and R ² and R ³ are united with the adjacent nitrogen atom to be substituted with carboxyl-piperidine- Process for the preparation of compounds of formula (I) which are 1-yl

[The symbol in a formula shows the above-mentioned meaning. ]
In this production method, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, alcohol (such as methanol (MeOH), ethanol (EtOH), 2-propanol) or water, or a mixture thereof is used. This is a method for producing a compound (I) according to an object of the production method of the present invention by acting on the compound (2A) in a solvent and subjecting it to a hydrolysis reaction. For the hydrolysis reaction, a method described in the above-mentioned Protective Groups in Organic Synthesis, a method according to them, or a method obvious to those skilled in the art can be used.
In addition, the compound (2A) which is a raw material compound of the present production method can be easily produced by a method according to the method described in the examples of the present specification, a method according thereto, a method obvious to those skilled in the art, or a combination thereof. can do. Moreover, the compound which concerns on the target object of the manufacturing method of this invention manufactured by the 1st manufacturing method may be used as a compound (2A) which is a raw material compound of this manufacturing method.

［式中の記号は上述の意味を示す。］
（工程Ａ）
本工程は、化合物（３Ａ）の脱離基Wを化合物（３Ｂ）で置換する工程である。化合物（３Ａ）における脱離基Wは、前述の通り、式（３Ｂ）で示されるアミン誘導体による置換反応において脱離基として機能する基であればいずれでもよく、具体的には例えば、フルオロ、クロロ等のハロゲン；メタンスルホニルオキシ、p-トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等のスルホニルオキシ基を挙げることができる。好ましくは、フルオロ又はクロロである。
反応は、無溶媒中、又は芳香族炭化水素類；エーテル類；ハロゲン化炭化水素類；DMF；DMSO；N-メチルピロリドン；エステル類；アセトニトリル等の反応に不活性な溶媒、又はアルコール類中、化合物（３Ａ）と化合物（３Ｂ）とを等モル乃至一方を過剰量用い、室温乃至加熱還流下に行うことができる。化合物によっては、トリエチルアミン、ジイソプロピルアミン、N-メチルモルホリン、ピリジン、ジメチルアミノピリジン等の有機塩基、及び／又は炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水素化ナトリウム等の金属塩塩基の存在下に行うのが有利な場合がある。
（工程Ｂ）
本工程は、R^3B2が保護された-OH若しくは保護されたアミノである場合に、その保護基を脱離させる工程である。この保護基の脱離は、反応は、上述のProtective Groups in Organic Synthesisに記載の方法や、それらに準じた方法、又は当業者にとって自明である方法を用いることができる。
なお、本製造法の原料化合物である化合物（３Ａ）は、本願明細書実施例記載の方法のほか、それに準じた方法、当業者にとって自明である方法、又はそれらを組み合わせることにより、容易に製造することができる。
（第４製法）-A=が-N=であり、従って-Y-が-NR³-であり、-R²が低級アルキルスルホニルアミノで置換されている低級アルキルであり、-R³が-H、若しくは低級アルキルである、式（Ｉ）の化合物の製造法

［式中、R¹、X、R^4A、R³は前述の意味を示し、R^4Bは低級アルキルスルホニルアミノで置換されている低級アルキルを示す。］
本製法は、化合物（４Ａ）のR^4Aにおけるアミノ基を、低級アルキルスルホニル化剤を用いて低級アルキルスルホニル化することにより、本発明の製造法の目的物に係る化合物（Ｉ）を製造する方法である。低級アルキルスルホニル化は、上述のProtective Groups in Organic Synthesisに記載の方法や、それらに準じた方法、又は当業者にとって自明である方法を用いることができる。
なお、本製造法の原料化合物である化合物（４Ａ）は、本願明細書実施例記載の方法のほか、それに準じた方法、当業者にとって自明である方法、又はそれらを組み合わせることにより、容易に製造することができる。また、第３製法で製造した本発明の製造法の目的物に係る化合物が、本製造法の原料化合物である化合物（４Ａ）として用いられることもある。
（第５製法）-A=が-CH=であり、従って-Y-が-O-である、式（Ｉ）の化合物の製造法

［式中の記号は前述の意味を示す。］
（工程Ａ）
本工程は、第１製法工程Ａに準じて行うことができる。
（工程Ｂ、工程Ｃ）
本工程は、第１製法工程Ｂ及び／又は工程Ｃに準じて行うことができる。
（工程Ｄ、工程Ｅ）
本工程は、第３製法工程Ｂに準じて行うことができる。
なお、本製造法の原料化合物である化合物（５Ａ）は、本願明細書実施例記載の方法のほか、それに準じた方法、当業者にとって自明である方法、又はそれらを組み合わせることにより、容易に製造することができる。 (Third Production Method) -A = is -N =, therefore -Y- is -NR ^3- , and -R ² is a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino. A substituted lower alkyl and -R ³ is -H or a lower alkyl compound of formula (I); or -A = is -N = and thus -Y- is -NR ^3- Wherein R ² and R ³ are piperazin-1-yl substituted with an adjacent nitrogen atom and substituted with an oxo group, a process for the preparation of a compound of formula (I)

[The symbol in a formula shows the above-mentioned meaning. ]
(Process A)
This step is a step of substituting the leaving group W of the compound (3A) with the compound (3B). As described above, the leaving group W in the compound (3A) may be any group as long as it functions as a leaving group in the substitution reaction with the amine derivative represented by the formula (3B). Halogens such as chloro; sulfonyloxy groups such as methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like can be mentioned. Preferably, it is fluoro or chloro.
The reaction is carried out in the absence of a solvent, or in an aromatic hydrocarbon; ethers; halogenated hydrocarbons; DMF; DMSO; N-methylpyrrolidone; esters; Compound (3A) and compound (3B) can be used in an equimolar amount or in an excess amount of one, and can be performed at room temperature or under heating and reflux. Depending on the compound, it is carried out in the presence of an organic base such as triethylamine, diisopropylamine, N-methylmorpholine, pyridine, dimethylaminopyridine, and / or a metal salt base such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride. May be advantageous.
(Process B)
This step is a step of removing the protecting group when R ^3B2 is protected —OH or protected amino. For the removal of this protecting group, the reaction can be carried out by the method described in the above-mentioned Protective Groups in Organic Synthesis, a method according to them, or a method obvious to those skilled in the art.
In addition, the compound (3A) which is a raw material compound of this production method is easily produced by a method according to the method described in the examples of the present specification, a method according thereto, a method obvious to those skilled in the art, or a combination thereof. can do.
(Fourth Production Process) -A = is -N =, therefore -Y- is -NR ^3- , -R ² is lower alkyl substituted with lower alkylsulfonylamino, and -R ³ is- Process for the preparation of a compound of formula (I) which is H or lower alkyl

[Wherein R ¹ , X, R ^4A and R ³ represent the above-mentioned meanings, and R ^4B represents lower alkyl substituted with lower alkylsulfonylamino. ]
In this production method, the amino group in R ^4A of compound (4A) is subjected to lower alkylsulfonylation using a lower alkylsulfonylating agent to produce compound (I) according to the object of the production method of the present invention. It is. For the lower alkylsulfonylation, a method described in the above-mentioned Protective Groups in Organic Synthesis, a method according to them, or a method obvious to those skilled in the art can be used.
In addition, the compound (4A), which is a raw material compound of this production method, can be easily produced by the methods described in the examples of this application, a method according thereto, a method obvious to those skilled in the art, or a combination thereof. can do. Moreover, the compound which concerns on the target object of the manufacturing method of this invention manufactured by the 3rd manufacturing method may be used as a compound (4A) which is a raw material compound of this manufacturing method.
(Fifth Production Process) A process for producing a compound of formula (I), wherein -A = is -CH = and therefore -Y- is -O-.

[The symbols in the formula have the above-mentioned meanings. ]
(Process A)
This step can be performed according to the first production method step A.
(Process B, Process C)
This process can be performed according to the 1st manufacturing method process B and / or process C.
(Process D, Process E)
This step can be performed according to the third production step B.
In addition, the compound (5A) which is a raw material compound of the present production method can be easily produced by a method according to the method described in the examples of the present specification, a method according thereto, a method obvious to those skilled in the art, or a combination thereof. can do.

  Furthermore, some of the compounds represented by the formula (I) are known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, etc. from the compound according to the object of the production method of the present invention obtained as described above. It can also be produced by arbitrarily combining processes that can be usually employed by those skilled in the art, such as decomposition.

The compound thus produced, which is the object of the production method of the present invention, is isolated or purified as a salt after being free or subjected to a salt formation treatment by a conventional method. Isolation / purification is performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by conventional methods utilizing differences in physicochemical properties between isomers. For example, a racemic mixture can be led to an optically pure isomer by a common racemic resolution method, such as a method for optical resolution by diastereomeric salts with common optically active acids such as tartaric acid. . The diastereo mixture can be separated by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

A medicament comprising a compound that is the target of the production method of the present invention as an active ingredient is usually used for formulating one or more of the compounds that are the target of the production method of the present invention represented by formula (I), It can be prepared by a commonly used method using a pharmaceutical carrier, excipient, and other additives. Administration is any of oral administration using tablets, pills, capsules, granules, powders, liquids, injections such as intravenous injection and intramuscular injection, or parenteral administration using suppositories, nasal, transmucosal, transdermal, etc. It may be a form.
As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. Mixed with magnesium acid etc. The composition contains additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium calcium glycolate, a stabilizer, a solubilizing agent and the like according to a conventional method. May be. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or a gastric or enteric film.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. , Ethanol (EtOH). In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as EtOH, polysorbate 80, and the like. Such a composition may further contain auxiliary agents such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

  Usually, in the case of oral administration, the daily dose is about 0.0001 to 50 mg / kg per body weight, preferably about 0.001 to 10 mg / kg, more preferably 0.01 to 1 mg / kg, This is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dose is about 0.0001 to 1 mg / kg, preferably about 0.0001 to 0.1 mg / kg per body weight, and is administered once a day or divided into multiple times. The dosage is appropriately determined according to individual cases in consideration of symptoms, age, sex and the like.

  EXAMPLES Hereinafter, the production method of the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples. In addition, the raw material compound used in an Example also contains a novel substance, The manufacturing method from the well-known thing of such a raw material compound is demonstrated as a reference example.

Reference example 1
Bromine was added to an ether solution of 4-chloro-2-acetylthiophene under ice cooling, followed by stirring at room temperature for 2 hours to obtain a bromide. Thiourea was added to the bromide EtOH solution at room temperature and stirred overnight at 80 ° C. to obtain 2-amino-4- (4-chlorothiophen-2-yl) thiazole.
FAB-MS (M + H) ⁺ : 217.

Reference example 2
To the pyridine suspension of Reference Example 1 and 5,6-dichloronicotinic acid, phosphorus oxychloride was added at −30 ° C., the temperature was gradually raised, and the mixture was stirred overnight at room temperature, and 5,6-dichloro-N— [4- (4-Chlorothiophen-2-yl) thiazol-2-yl] nicotinamide was obtained.
In the same manner as in Reference Example 2, Reference Example 3 shown in Table 3 was produced using the corresponding raw materials.

The symbols in the table have the following meanings (the same applies hereinafter).
Rf: Reference example number.
Data: Physical data (MS: FAB-MS (M + H) ⁺ ).
R: Substituent in the general formula (Py: pyridyl, Ac: acetyl, Ph: phenyl, di: di. The number before the substituent indicates the position of substitution, and thus, for example, 5,6-diCl-3-Py is 5,6-dichloropyridin-3-yl is shown.)

Reference example 4
To a THF solution of the compound of Reference Example 2, triethylamine and ethyl isonipecotate were added, and the mixture was stirred overnight at 50 ° C. to give 1- (3-chloro-5-{[4- (4-chlorothiophen-2-yl) Thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid ethyl ester was obtained.
FAB-MS (M + H) ⁺ : 511.

Reference Example 5
Acetic acid, an aqueous formaldehyde solution (36%), and N-butyl-N-methylamine were added to the compound of Reference Example 2, and the mixture was stirred at 80 ° C. overnight. N- [5-{[butyl (methyl) amino] methyl} -4- (4-Chlorothiophen-2-yl) thiazol-2-yl] -5,6-dichloronicotinamide was obtained.
FAB-MS (M + H) ⁺ : 489.

Reference Example 6
To a DMF solution of 2,6-dichloro-5-fluoronicotinic acid, add ethyl isonipecotate and stir at 80 ° C. to give 2-chloro-6- [4- (ethoxycarbonyl) piperidin-1-yl] -5- Fluoronicotinic acid was obtained.
FAB-MS (M + H) ⁺ : 331.

Reference Example 7
To a THF-EtOH solution of the compound of Reference Example 6 were added triethylamine and 10% palladium on carbon, and the mixture was stirred at room temperature in a 4 atmosphere hydrogen atmosphere to give 6- [4- (ethoxycarbonyl) piperidin-1-yl]- 5-fluoronicotinic acid was obtained.
FAB-MS (M + H) ⁺ : 297.

Reference Example 8
To the pyridine suspension of the compound of Reference Example 1 and the compound of Reference Example 7, phosphorus oxychloride is added at −30 ° C., the temperature is gradually raised, and the mixture is stirred overnight at room temperature, and 1- (5-{[4- ( 4-Chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -3-fluoro-2-pyridyl) piperidine-4-carboxylic acid ethyl ester was obtained.
FAB-MS (M + H) ⁺ : 495.

Example 1
To 150 mg of the compound of Reference Example 4, 3 ml of acetic acid, 24 μl of an aqueous formaldehyde solution (36%) and 47 μl of N-butyl-N-methylamine were added and stirred at 90 ° C. for 18 hours. After evaporating the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography using hexane: EtOAc (7: 1 to 5: 1) as an elution solvent, and 1- (5-{[5-{[butyl 147 mg of (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -3-chloro-2-pyridyl) piperidine-4-carboxylic acid ethyl ester was obtained. .

Example 2
To a suspension of 2300 mg of the compound of Example 1 in 30.0 ml of EtOH was added 11.3 ml of 1M aqueous sodium hydroxide solution, and the mixture was stirred at 50 ° C. for 2 hours. At room temperature, 11.3 ml of 1M aqueous hydrochloric acid was added, and the resulting precipitate was collected by filtration, washed with 50% aqueous ethanol, and dried under reduced pressure. 1200 mg of the obtained solid was dissolved in 120 ml of 50% acetonitrile aqueous solution, 3.2 ml of 1M hydrochloric acid aqueous solution was added at room temperature, and after stirring for 5 hours, the resulting precipitate was collected by filtration and washed with 50% ethanol aqueous solution. The obtained solid was dried under reduced pressure, and 1- (5-{[5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl}- 3-Chloro-2-pyridyl) piperidine-4-carboxylic acid hydrochloride 950 mg was obtained.

Example 3
Ethane-1,2-diamine (184 mg) and triethylamine (0.17 ml) were added to a THF (6 ml) solution of the compound of Reference Example 5 (300 mg), and the mixture was stirred at 50 ° C. for 1 day. 736 mg of ethane-1,2-diamine was added, and the mixture was further stirred for 8 hours. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography using EtOAc, followed by chloroform: MeOH = 10: 1 as an elution solvent, and 6-[(2-aminoethyl) amino] -N 290 mg of-[5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloronicotinamide was obtained.

Example 4
290 mg of the compound of Example 3 was dissolved in 10 ml of THF, 315 μl of triethylamine was added, and the mixture was cooled to 0 ° C. To the solution, 48 μl of methanesulfonyl chloride was added and stirred at room temperature for 1 hour. The reaction mixture was poured into water, extracted with chloroform, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: MeOH = 10: 1), 4M hydrogen chloride-dioxane solution was added and stirred, the resulting precipitate was collected by filtration, dried under reduced pressure, and 279 mg of N- [5 -{[Butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloro-6-({2-[(methylsulfonyl) amino] ethyl} Amino) nicotinamide hydrochloride was obtained.

Tables 4-7 below show the structures and physical data of the example compounds. The symbols in the table have the following meanings (the same applies hereinafter).
Ex: Example number (When only a number is described in the column of Ex, it indicates that the compound of the example number is a free form, and a slash (/) and “HCl” following the number are described. The case indicates that the compound of that example number is the hydrochloride salt).
Syn: Production method (numbers indicate synthesis using corresponding raw materials in the same manner as Example compounds having the numbers as Example numbers).
R: Substituent in formula (Me: methyl, Et: ethyl, cPr: cyclopropyl, iPr: isopropyl, nBu: normal butyl, cBu: cyclobutyl, iBu: isobutyl, Ms: methanesulfonyl, pipa: piperazine-1- Il, oxo).

Table 8 below shows the NMR data for some example compounds. The data show δ (ppm) of a peak in ¹ H-NMR using tetramethylsilane as an internal standard and DMSO-d ₆ as a measurement solvent unless otherwise specified.

Claims (5)

Compound of formula (I)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-A =: -N = or -CH =.
-X: Halogen.
-Y - :( a) if -A = is -N =, -NR ³ -. (B) -O- when -A = is -CH =.
-R ^2: -OH, amino, and lower alkyl substituted by a group selected from the group consisting of lower alkylsulfonylamino.
-R ³ : -H or lower alkyl.
Alternatively, R ² and R ³ together with the adjacent nitrogen atom are substituted with a group selected from the group consisting of carboxyl and —CO ₂ -lower alkyl; or substituted with an oxo group Piperazin-1-yl; ]
Or a pharmaceutically acceptable salt thereof,
-A = is -N =, and therefore -Y- is -NR ^3- , and R ² and R ³ together with the adjacent nitrogen atom are substituted with -CO ₂ -lower alkyl-piperidine- A process for producing a compound which is 1-yl or a pharmaceutically acceptable salt thereof,
Compound of formula (1A)

[The symbols in the formula have the following meanings.
-X: Halogen.
-R ^1A : Lower alkyl. ]
A process comprising introducing an NR ¹ -N-methylaminomethyl group with respect to Compound of formula (I)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-A =: -N = or -CH =.
-X: Halogen.
-Y - :( a) if -A = is -N =, -NR ³ -. (B) -O- when -A = is -CH =.
-R ^2: -OH, amino, and lower alkyl substituted by a group selected from the group consisting of lower alkylsulfonylamino.
-R ³ : -H or lower alkyl.
Alternatively, R ² and R ³ together with the adjacent nitrogen atom are substituted with a group selected from the group consisting of carboxyl and —CO ₂ -lower alkyl; or substituted with an oxo group Piperazin-1-yl; ]
Or a pharmaceutically acceptable salt thereof,
-A = is -N =, thus -Y- is -NR ^3- , and R ² and R ³ are piperidin-1-yl substituted with a carboxyl together with the adjacent nitrogen atom A process for producing a compound or a pharmaceutically acceptable salt thereof, comprising:
Compound of formula (2A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-R ^2A: lower alkyl. ]
The manufacturing method including attaching | subjecting to hydrolysis reaction. Compound of formula (I)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-A =: -N = or -CH =.
-X: Halogen.
-Y - :( a) if -A = is -N =, -NR ³ -. (B) -O- when -A = is -CH =.
-R ^2: -OH, amino, and lower alkyl substituted by a group selected from the group consisting of lower alkylsulfonylamino.
-R ³ : -H or lower alkyl.
Alternatively, R ² and R ³ together with the adjacent nitrogen atom are substituted with a group selected from the group consisting of carboxyl and —CO ₂ -lower alkyl; or substituted with an oxo group Piperazin-1-yl; ]
Or a pharmaceutically acceptable salt thereof,
-A = is -N =, thus -Y- is -NR ^3- , and -R ² is substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino A compound that is alkyl and —R ³ is —H, or lower alkyl, or a pharmaceutically acceptable salt thereof; or —A═ is —N═ and thus —Y— is —NR ³ — A method for producing a compound or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are combined with an adjacent nitrogen atom and are piperazin-1-yl substituted with an oxo group,
Compound of formula (3A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-W: leaving group. ]
Against the compound of formula (3B)

[The symbols in the formula have the following meanings.
-R ^3B2 : lower alkyl substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino. In addition, when the lower alkyl substituent is —OH or amino, these groups may be protected.
-R ^3B3 : -H or lower alkyl.
Alternatively, R ^3B2 and R ^3B3 may be combined with an adjacent nitrogen atom to represent piperazin-1-yl substituted with an oxo group. ]
And when R ^3B2 is protected —OH or protected amino, the method further comprises removing the protecting group. Compound of formula (I)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-A =: -N = or -CH =.
-X: Halogen.
-Y - :( a) if -A = is -N =, -NR ³ -. (B) -O- when -A = is -CH =.
-R ^2: -OH, amino, and lower alkyl substituted by a group selected from the group consisting of lower alkylsulfonylamino.
-R ³ : -H or lower alkyl.
Alternatively, R ² and R ³ together with the adjacent nitrogen atom are substituted with a group selected from the group consisting of carboxyl and —CO ₂ -lower alkyl; or substituted with an oxo group Piperazin-1-yl; ]
Or a pharmaceutically acceptable salt thereof,
-A = is -N =, therefore -Y- is -NR ^3- , -R ² is lower alkyl substituted with lower alkylsulfonylamino, -R ³ is -H, or lower alkyl Or a pharmaceutically acceptable salt thereof, comprising the steps of:
Compound of formula (4A)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-X: Halogen.
-R ^4A : Lower alkyl substituted with amino.
-R ³ : -H or lower alkyl. ]
On the other hand, the manufacturing method including making a lower alkyl sulfonylating agent act. Compound of formula (I)

[The symbols in the formula have the following meanings.
-R ¹ : lower alkyl or cycloalkyl.
-A =: -N = or -CH =.
-X: Halogen.
-Y - :( a) if -A = is -N =, -NR ³ -. (B) -O- when -A = is -CH =.
-R ^2: -OH, amino, and lower alkyl substituted by a group selected from the group consisting of lower alkylsulfonylamino.
-R ³ : -H or lower alkyl.
Alternatively, R ² and R ³ together with the adjacent nitrogen atom are substituted with a group selected from the group consisting of carboxyl and —CO ₂ -lower alkyl; or substituted with an oxo group Piperazin-1-yl; ]
Or a pharmaceutically acceptable salt thereof,
A process for producing a compound or a pharmaceutically acceptable salt thereof, wherein -A = is -CH = and -Y- is -O-,
Compound of formula (5A)

[The symbols in the formula have the following meanings.
-X: Halogen.
-R ^5A : lower alkyl substituted with a group selected from the group consisting of -OH, amino, and lower alkylsulfonylamino. In addition, when the lower alkyl substituent is —OH or amino, these groups may be protected. ]
A method comprising introducing an NR ¹ -N-methylaminomethyl group to R5A and further removing the protective group when R ^5A is protected —OH or protected amino.