JP4774995B2 - Pharmaceutical composition comprising an acylaminothiazole derivative as an active ingredient - Google Patents

Description

  The present invention relates to a pharmaceutical composition comprising, as an active ingredient, a novel 2-acylaminothiazole derivative or a salt thereof useful as a pharmaceutical, particularly a thrombocytopenia therapeutic agent.

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, 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), 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本発明の医薬組成物の有効成分に係る化合物中のR³が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位が窒素原子で置換された低級アルキル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, in the present invention, R ³ in the compound relating to the active ingredient of the pharmaceutical composition of the present invention is not substituted with a substituent having an A ¹ group such as thiazolyl group in the publication. In addition, in this publication, there is no specific disclosure in any way regarding the compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom.

（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、本発明においては、該公報におけるW¹基を有する置換基で本発明の医薬組成物の有効成分に係る化合物中のR³が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位が窒素原子で置換された低級アルキル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, in the present invention, R ³ in the compound relating to the active ingredient of the pharmaceutical composition of the present invention is not substituted with the substituent having the W ¹ group in the publication. In addition, in this publication, there is no specific disclosure in any way regarding the compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom.

（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、本発明におけるチアゾール5位が窒素原子で置換された低級アルキルで置換されている化合物については言及されていない。 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 mention of a compound in which the 5-position of thiazole in the present invention is substituted with a lower alkyl substituted with a nitrogen atom.

（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、本発明におけるチアゾール5位が窒素原子で置換された低級アルキルで置換されている化合物については言及されていない。 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 mention of a compound in which the 5-position of thiazole in the present invention is substituted with a lower alkyl substituted with a nitrogen atom.

In addition to the above Patent Documents 7 to 10, 2-acylaminothiazole compounds are disclosed in Japanese Patent No. 3199451 (Patent Document 11) as cholecystokinin and gastrin receptor antagonists, or in Chemical and Pharmaceutical Bulletin, 25, 9, 2292-2299, 1977 (Non-patent Document 5) discloses compounds having anti-inflammatory properties, but none of them mentions the platelet-increasing action according to the present invention.
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 Japanese Patent No. 3199451 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 Chemical and Pharmaceutical Bulletin, 1977, 25, 9, p.2292-2299

  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.

［式中の記号は以下の意味を示す。
B：低級アルキレン。
R⁴：式（ＩＩ）で示される基、又は置換されていてもよい環状アミノ。

［式中の記号は以下の意味を示す。
R¹¹：H、置換されていてもよい低級アルキル、又は置換されていてもよいシクロアルキル。なお、Bがメチレンを示す場合、R¹¹は、R⁵で示されるチエニル若しくはフェニルへ架橋するメチレンとして存在してもよい。また、Bがメチレンを示す場合、R¹¹は、Bで示されるメチレンへ閉環する置換されていてもよい低級アルキレンとして存在していてもよい。
R¹²：それぞれ置換されていてもよい低級アルキル、シクロアルキル若しくは非芳香族ヘテロ環。］
R⁵：それぞれ置換されていてもよいチエニル若しくはフェニル。
R⁶：それぞれ置換されていてもよい芳香族ヘテロ環、アリール若しくは環状アミノ。但し、置換されていないフェニル及び置換されていてもよいインドールを除く。］ As a result of intensive research on a compound that is a c-Mpl ligand that can be expected to be effective against thrombocytopenia, the present inventors have found that a novel 2-acylaminothiazole derivative has an excellent effect, and found the present invention. Completed.
That is, according to the present invention, the following (1) to (9) are provided.
(1) A pharmaceutical composition comprising a 2-acylaminothiazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[The symbols in the formula have the following meanings.
B: Lower alkylene.
R ⁴ : a group represented by the formula (II), or an optionally substituted cyclic amino.

[The symbols in the formula have the following meanings.
R ¹¹ : H, optionally substituted lower alkyl, or optionally substituted cycloalkyl. When B represents methylene, R ¹¹ may exist as methylene that bridges to thienyl or phenyl represented by R ⁵ . Further, when B represents methylene, R ¹¹ may be present as an optionally substituted lower alkylene that cyclizes to the methylene represented by B.
R ¹² : lower alkyl, cycloalkyl or non-aromatic heterocycle, each optionally substituted. ]
R ⁵ : each optionally substituted thienyl or phenyl.
R ⁶ : Aromatic hetero ring, aryl or cyclic amino, each optionally substituted. However, unsubstituted phenyl and indole which may be substituted are excluded. ]

(2) The pharmaceutical composition of (1), wherein B is methylene.
(3) R ⁵ is lower alkyl optionally substituted with one or more halogens, and thienyl or phenyl substituted with one or more groups selected from the group consisting of halogens, (2) Pharmaceutical composition.
(4) The pharmaceutical composition according to (3), wherein R ⁶ is optionally substituted pyridyl or substituted phenyl.
(5) R ⁶ is selected from the group consisting of pyridine-3-yl substituted at the 5-position with a group selected from the group consisting of chloro and fluoro, and further substituted at the 6-position, or chloro and fluoro The pharmaceutical composition according to (4), which is phenyl substituted at the 3-position with a group, substituted at the 5-position with a group selected from the group consisting of -H, chloro and fluoro, and further substituted at the 4-position.

(6) A pharmaceutical composition comprising, as an active ingredient, a compound selected from the group consisting of compound group X and compound group Y among the pharmaceutical compositions of (1). Preferably, a pharmaceutical composition comprising a compound selected from compound group X as an active ingredient.
Here, “compound group X” means
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[cyclobutyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} piperidine -4-carboxylic acid,
1- (5-{[5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -3-chloro-2-pyridyl) piperidine -4-carboxylic acid,
1- {5-[(4- (4-Chlorothiophen-2-yl) -5-{[(2R) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl] -3- Fluoro-2-pyridyl} piperidine-4-carboxylic acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2S) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl ] -2-pyridyl} piperidine-4-carboxylic acid,
1- (3-Chloro-5-{[4- (4-chlorothiophen-2-yl) -5- (dimethylaminomethyl) thiazol-2-yl] carbamoyl} -2-pyridyl) piperidine-4-carboxylic acid ,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[isopropyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} piperidine -4-carboxylic acid,
4-[{3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[isopropyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} (Methyl) amino] butyric acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(3S) -3-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl ] -2-pyridyl} piperidine-4-carboxylic acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[[(2S) -2-methoxypropyl] (methyl) amino] methyl} thiazol-2-yl ) Carbamoyl] -2-pyridyl} piperidine-4-carboxylic acid,
N- [5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloro-6-[(3-hydroxypropyl) amino] Nicotinamide,
N- [5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloro-6- (3-oxopiperazin-1-yl ) Nicotinamide and
N- [5-{[Butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloro-6- [4- (hydroxymethyl) piperidino] Nicotinamide,
And a compound group consisting of these pharmaceutically acceptable salts,
"Compound group Y"
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2R) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl ] -2-pyridyl} piperidine-4-carboxylic acid,
4-[{3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2R) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) Carbamoyl] -2-pyridyl} (methyl) amino] butyric acid,
4-[{3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2S) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) Carbamoyl] -2-pyridyl} (methyl) amino] butyric acid,
1- {5-[(4- (4-Chlorothiophen-2-yl) -5-{[(2S) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl] -3- Fluoro-2-pyridyl} piperidine-4-carboxylic acid,
(1- {3-chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2R) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) Carbamoyl] -2-pyridyl} azetidin-3-yl) acetic acid,
(1- {3-chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2S) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) Carbamoyl] -2-pyridyl} azetidin-3-yl) acetic acid,
1- (3-Chloro-5-{[5-{[isopropyl (methyl) amino] methyl} -4- (4-methylthiophen-2-yl) thiazol-2-yl] carbamoyl} -2-pyridyl) piperidine -4-carboxylic acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(3R) -3-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl ] -2-pyridyl} piperidine-4-carboxylic acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[[(2R) -2-methoxypropyl] (methyl) amino] methyl} thiazol-2-yl ) Carbamoyl] -2-pyridyl} piperidine-4-carboxylic acid,
1- (5-{[5- (azepan-1-ylmethyl) -4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -3-chloro-2-pyridyl) piperidine-4- carboxylic acid,
1- {3-chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} thiazol-2-yl) carbamoyl]- 2-pyridyl} piperidine-4-carboxylic acid,
1- (5-{[5- (Azocan-1-ylmethyl) -4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -3-chloro-2-pyridyl) piperidine-4- carboxylic acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[cyclohexyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} piperidine -4-carboxylic acid, and
1- {3-chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[cyclopropyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} Piperidine-4-carboxylic acid,
In addition, it is a compound group consisting of these pharmaceutically acceptable salts.

(7) The pharmaceutical composition according to any one of (1) to (6), which is a platelet increasing agent.
(8) The pharmaceutical composition according to any one of (1) to (6), which is a therapeutic agent for thrombocytopenia.
(9) The pharmaceutical composition according to any one of (1) to (6), which is a c-Mpl ligand.

In the compound represented by formula (I), B is preferably methylene.
Further, R ⁴ in the compound represented by the formula (I) is preferably a group represented by the formula (II) wherein R ¹¹ is lower alkyl and R ¹² is an optionally substituted lower alkyl or cycloalkyl. Or a cyclic amino optionally substituted with lower alkyl; and more preferably represented by formula (II) wherein R ¹¹ is methyl and R ¹² is an optionally substituted lower alkyl or cycloalkyl, respectively. Or a cyclic amino optionally substituted with methyl.

Further, R ⁵ in the compound represented by the formula (I) is preferably an optionally substituted thienyl; more preferably, a lower alkyl optionally substituted with one or more halogens, and a halogen. Thienyl substituted with one or more substituents selected from the group consisting of; more preferably thienyl substituted with one or more groups selected from the group consisting of chloro and methyl; 4-chlorothiophen-2-yl or 4-methylthiophen-2-yl is preferred. In addition, another preferred embodiment of R ^{5 in} the compound represented by the formula (I) includes phenyl which may be substituted; more preferably, it may be substituted with one or more halogens. Phenyl substituted with one or more groups selected from the group consisting of lower alkyl and halogen; more preferably substituted with one or more groups selected from the group consisting of trifluoromethyl, chloro and fluoro Particularly preferred is 3-trifluoromethylphenyl, 4-fluorophenyl or 3-chlorophenyl.

In addition, R ⁶ in the compound represented by the formula (I) is preferably an optionally substituted pyridyl; more preferably a pyridyl substituted with at least one halogen; and more preferably chloro and Pyridin-3-yl substituted at the 5-position with a group selected from the group consisting of fluoro and further substituted at the 6-position. Among them, piperidin-1-yl or piperazine-1 each optionally substituted with one or more groups selected from the group consisting of lower alkyl substituted with substituent group W, substituent group W and oxo -Oil; and -O-lower alkyl, -NH-lower alkyl, or -N (lower alkyl) -lower alkyl, each optionally substituted with one or more groups selected from substituent group W Pyridin-3-yl substituted at the 6-position with a more selected group and substituted at the 5-position with a group selected from the group consisting of chloro and fluoro is preferred.

Here, the “substituent group W” is substituted with —OH, —OR ^Z , —OCO—R ^Z , carboxyl, —CO ₂ —R ^Z , —CO—R ^Z , or one or two R ^Z. Optionally substituted carbamoyl (if substituted with two R ^Z they may be the same or different), cyano, optionally substituted with one or two R ^Z amino (with two R ^Z When substituted, they may be the same or different), —NHCO—R ^Z , —NHSO ₂ —R ^Z , sulfamoyl optionally substituted with one or two R ^Z (with two R ^Z When substituted, they may be the same or different), —SO ₃ H, —P (O) (OH) ₂ , —P (O) (OH) (OR ^Z ), —P (O) ( OR ^Z ) ₂ (each R ^Z may be the same or different), and represents a group consisting of an aromatic heterocycle, a non-aromatic heterocycle and R ^Z , and “R ^Z ” -OH, -O-lower alkyl (this lower alkyl is derived from -OH, -O-lower alkyl and amino May be substituted with one or more groups selected from the group consisting), - OCO- lower alkyl, carboxyl, -CO ₂ - lower alkyl, -CO- lower alkyl, substituted with one or two lower alkyl Optionally substituted carbamoyl (if substituted with two lower alkyls they may be the same or different), cyano, optionally substituted with one or two lower alkyls (two lower alkyls) They may be the same or different), —NHCO-lower alkyl, —NHSO ₂ -lower alkyl, sulfamoyl optionally substituted with one or two lower alkyls (two lower alkyls) They may be the same or different), —SO ₃ H, —P (O) (OH) ₂ , —P (O) (OH) (O-lower alkyl), —P ( O) (O-lower alkyl) ₂ (each lower alkyl is the same or different To lower alkyl, cycloalkyl or non-aromatic optionally substituted with one or more groups selected from the group consisting of aromatic heterocycles, non-aromatic heterocycles and halogens. Indicates a terror ring (the same applies hereinafter).

In addition, another preferred embodiment of R ^{6 in} the compound represented by the formula (I) can include optionally substituted phenyl; more preferably, it is phenyl substituted with at least one halogen; More preferably, the 3-position is substituted with a group selected from the group consisting of chloro and fluoro, the 5-position is substituted with a group selected from the group consisting of -H, chloro and fluoro, and the 4-position is further substituted. Phenyl. Among them, piperidin-1-yl or piperazine-1 each optionally substituted with one or more groups selected from the group consisting of lower alkyl substituted with substituent group W, substituent group W and oxo -Oil; and -O-lower alkyl, -NH-lower alkyl, or -N (lower alkyl) -lower alkyl, each optionally substituted with one or more groups selected from substituent group W The 4-position is substituted with a group selected from the above, the 3-position is substituted with a group selected from the group consisting of chloro and fluoro, and the 5-position is substituted with a group selected from the group consisting of -H, chloro and fluoro. Preferred is phenyl.

Note that "when the B represents a methylene, R ¹¹ is present may be a methylene bridging to thienyl or phenyl represented by R ^5" in R ¹¹ and, specifically, for example, as listed in Table 31 It is meant to indicate the partial structure of the compound.

The compound according to the active ingredient of the pharmaceutical composition of the present invention is a 2-acylaminothiazole derivative substituted at the 2-position with a lower alkyl substituted with an acylamino group and at the 5-position with a nitrogen atom. Has structural features. In addition, the compound according to the active ingredient of the pharmaceutical composition of the present invention has human c-mpl-Ba / F3 cell proliferation activity, human CD34 ⁺ cell differentiation promoting activity into megakaryocytes, and good oral administration test in mice. It exhibits activity and, as a result, has pharmacological characteristics in that it has a platelet-increasing action.

  The compound according to the active ingredient of the pharmaceutical composition of the present invention has an excellent platelet-increasing action. Therefore, the pharmaceutical composition of the present invention is aplastic anemia, thrombocytopenia in myelodysplastic syndrome, chemotherapy of malignant tumor, thrombocytopenia due to radiotherapy, idiopathic thrombocytopenic purpura, thrombocytopenia in liver disease It is useful for the treatment and / or prevention of various thrombocytopenia such as thrombocytopenia caused by HIV, and when there is a possibility that thrombocytopenia may occur due to chemotherapy or radiotherapy, it should be done before the treatment. It can also be administered.

The compound according to the active ingredient of the pharmaceutical composition 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.
The “lower alkylene” is a C _1-6 alkyl divalent group, preferably a C _1-4 alkylene methylene, ethylene, trimethylene, methylethylene, tetramethylene, dimethylmethylene, dimethylethylene, more preferably Methylene and ethylene, with methylene being particularly preferred.

“Cycloalkyl” means a C _3-8 carbocyclic ring which may be partially unsaturated. Therefore, specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclobutenyl, cyclohexenyl, cyclooctadienyl, and the like.
“Aryl” means a C _6-14 monocyclic to tricyclic aromatic ring, preferably phenyl or naphthyl, more preferably phenyl.

“Cyclic amino” has at least one nitrogen atom, and further has one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and having 3 to 8 ring members A monovalent group of a non-aromatic cyclic amine means a group in which at least one nitrogen atom has a bond. Specific examples include monovalent groups of azetidine, pyrrolidine, piperidine, azepan, azocan, azonan, azecan, piperazine, homopiperazine, morpholine, and thiomorpholine.
“Non-aromatic heterocycle” means a monovalent group of a non-aromatic heterocycle having one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. , Tetrahydrofuran, tetrahydropyran, tetrahydrothiofuran, tetrahydrothiopyran, oxetane, azetidine, pyrrolidine, piperidine, azepan, piperazine, homopiperazine, morpholine, thiomorpholine monovalent group, and the like.
“Aromatic heterocycle” means a 5- to 6-membered aromatic heterocycle having one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or a partially hydrogenated thereof This means a monovalent group of a ring, and specific examples include monovalent groups of pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, oxazole, thiazole, thiophene and furan. These rings may be condensed with a benzene ring.

  “Halogen” includes fluoro, chloro, bromo and iodo, preferably fluoro and chloro.

  In the present specification, the permissible substituents of the terms “optionally substituted” and “substituted” may be any substituents as long as they are usually used as a substituent of each group. One or more of these substituents may be present in each group.

"Cyclic amino which may be substituted" in R ^4, "optionally substituted cycloalkyl" in R ^11, "respectively optionally substituted cycloalkyl or non-aromatic hetero ring" in R ^12, R the permissible substituents in the "thienyl or phenyl which is substituted respectively" in ⁵ include the groups shown in the following (a) to (h).
(A) halogen;
^{(B) -OH, -OR Z,} -O- aryl, -OCO-R ^Z, oxo (= O);
(C) —SH, —SR ^Z , —S-aryl, —SO—R ^Z , —SO-aryl, —SO ₂ —R ^Z , —SO ₂ -aryl, substituted with one or two R ^Z Sulfamoyl (each R ^Z may be the same or different);
(D) amino optionally substituted with one or two R ^Z (when substituted with two R ^Z , each R ^Z may be the same or different), —NHCO— R ^Z, -NHCO- _{^{aryl, -NHCO 2 -R Z, -NHCONH 2}} , -NHSO 2 -R Z, -NHSO 2 - aryl, -NHSO ₂ NH _2, nitro;
(E) -CHO, -CO-R Z, -CO 2 H, -CO 2 -R Z, 1 or 2 R ^Z in substituted optionally carbamoyl, cyano;
(F) -OH, -O-lower alkyl, amino optionally substituted with one or two lower alkyls (when substituted with two lower alkyls, each lower alkyl may be the same or different Aryl or cycloalkyl each optionally substituted with one or more groups selected from the group consisting of halogen and R ^Z ;
(G) -OH, -O-lower alkyl, amino optionally substituted with one or two lower alkyls (when substituted with two lower alkyls, each lower alkyl may be the same or different An aromatic heterocycle or a non-aromatic heterocycle, each optionally substituted with one or more groups selected from the group consisting of halogen and R ^Z ;
(H) Lower alkyl which may be substituted with one or more groups selected from the substituents shown in the above (a) to (g).

Further, the "optionally substituted lower alkyl" for R ^11, the permissible substituents in "optionally substituted lower alkylene", "optionally substituted lower alkyl" for R ¹² is the Examples include groups represented by (a) to (g).

［式中の記号は、以下の意味を示す。
X：-OH、-O-低級アルキル、ハロゲン、オキソ及びR^Zからなる群より選択される１つ以上の基で置換されていてもよい環状アミンジイル。
Y：単結合、-O-低級アルキレン-、又は-N(低級アルキル)-低級アルキレン-。
Z：置換基群W、-環状アミンジイル-置換基群W、又は-CO-環状アミンジイル-置換基群W。］ Further, examples of the substituent allowed in the “aromatic heterocycle, aryl or cyclic amino each optionally substituted” for R ⁶ include halogen, lower alkyl optionally substituted with one or more halogens, — Examples include OH, —OR ^Z , oxo, amino optionally substituted with one or two R ^Z , and a group represented by the formula (III). Here, when the substituent is amino substituted with two R ^Z , the two R ^Z may be the same or different.

[The symbols in the formula have the following meanings.
X: Cyclic amine diyl optionally substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyl, halogen, oxo and R ^Z.
Y: Single bond, -O-lower alkylene-, or -N (lower alkyl) -lower alkylene-.
Z: Substituent group W, -Cyclic amine diyl-substituent group W, or -CO-Cyclic amine diyl-substituent group W. ]

  “Cyclic amine diyl” has at least one nitrogen atom and further has one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. This means a divalent group of a non-aromatic cyclic amine, in which at least one nitrogen atom has a bond. Specific examples include divalent groups such as azetidine, pyrrolidine, piperidine, azepan, azocan, azonan, azecan, piperazine, homopiperazine, morpholine, and thiomorpholine.

  The compound of the formula (I) which is an active ingredient of the pharmaceutical composition of the present invention may contain an asymmetric carbon atom depending on the kind of the substituent, and optical isomers based on this may exist. The present invention includes all pharmaceutical compositions containing a mixture of these optical isomers or an isolated one as an active ingredient. In addition, there may be a case where a tautomer exists in the compound related to the active ingredient of the pharmaceutical composition of the present invention. In the present invention, a pharmaceutical composition comprising a separated or mixture of these isomers as the active ingredient. Is included. In addition, a pharmaceutical composition containing as an active ingredient a label, that is, a compound in which one or more atoms of a compound relating to the active ingredient of the pharmaceutical composition of the present invention are substituted with a radioisotope or a non-radioisotope Is included.

  In addition, the compound according to the active ingredient of the pharmaceutical composition of the present invention may form a salt, and as long as the salt is a pharmaceutically acceptable salt, the compound is related to the active ingredient of the pharmaceutical composition of the present invention. Included in the compound. 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 is a pharmaceutical comprising as an active ingredient a compound which is an active ingredient of the pharmaceutical composition of the present invention, and various hydrates, solvates and crystal polymorphs of pharmaceutically acceptable salts thereof. Compositions are also included. The present invention includes all pharmaceutical compositions containing a compound that is metabolized in vivo and converted into the compound represented by formula (I) or a salt thereof, so-called prodrugs, as active ingredients. Examples of the group that forms a prodrug of the compound relating to the active ingredient of the pharmaceutical composition of the present invention include those described in Prog. Med. 5: 2157-2161 (1985), “Volume 7: Molecular Design, pages 163-198”.

(Production method)
The compound relating to the active ingredient of the pharmaceutical composition of the present invention and a pharmaceutically acceptable salt thereof are produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. can do. The typical production method is illustrated 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、R⁷はR¹¹がH、置換されていてもよい低級アルキル、又は置換されていてもよいシクロアルキルである前述の式（ＩＩ）で示される基、あるいは置換されていてもよい環状アミノを示し；R⁸は前述のR⁵で示される基を示し；R⁹は前述のR⁶で示される基、又は当業者が通常採用しうる方法によりR⁶に変換されうる基を示す。以下同様。）
本製造法は、式（Ｉ）で示される化合物のうち、Bがメチレンであり、R⁴とR⁵が架橋されておらず、R⁴とBが閉環していない化合物を製造する方法である。 (First manufacturing method)

(Wherein R ⁷ is a group represented by the above formula (II) in which R ¹¹ is H, optionally substituted lower alkyl, or optionally substituted cycloalkyl, or optionally substituted. R ⁸ represents a group represented by the above-mentioned R ⁵ ; R ⁹ represents a group represented by the above-mentioned R ⁶ , or a group that can be converted to R ⁶ by a method generally employed by those skilled in the art. The same shall apply hereinafter.)
This production method is a method for producing a compound represented by formula (I) wherein B is methylene, R ⁴ and R ⁵ are not bridged, and R ⁴ and B are not closed. .

(Process A)
This step is a step of producing compound (1c) by amidating compound (1b) or a reactive derivative thereof with compound (1a) or a salt thereof by a conventional method and removing a protecting group as necessary. is there.
As the amidation in this step, amidation which can be usually used by those skilled in the art can be adopted. Particularly, a method in which phosphorus oxychloride is allowed to act in a pyridine solvent, 1-ethylbenzotriazole (HOBt) in the presence of 1-ethyl A method in which a condensing agent such as -3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl cyanide, or the like is preferably used.
The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene; ether, tetrahydrofuran (THF), etc. Ethers of ethyl acetate (EtOAc) and the like; acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like in an organic solvent inert to the reaction, cooling, cooling to room temperature or It is carried out at room temperature or under heating.

(Process B)
In this step, an aminomethyl group is introduced into the thiazole 5-position of the compound (1c) using a Mannich reaction using the compound (1e), and the compound (I ). 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 C, Process D)
In this step, the acetoxymethyl group is introduced into the thiazole 5-position of the compound (1c) to form a compound (1d), and then a nucleophilic substitution reaction with the compound (1e) is performed under basic conditions. Is a step of producing a compound (I) according to the active ingredient.
The acetoxymethylation in Step C can be carried out by reacting compound (1c) with an aqueous formaldehyde solution or paraformaldehyde in an acetic acid solvent and at room temperature to heating, or from room temperature to reflux. In addition, in place of acetic acid solvent, acetic acid can be added and reacted in a solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc. There is a tendency to decrease. Further, the reaction can be carried out by further adding acetic anhydride.
The nucleophilic substitution reaction in Step D is carried out in an organic solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF, DMSO, etc. with respect to compound (1d). The reaction can be carried out by reacting compound (1e) in the presence of an organic base such as triethylamine or diisopropylethylamine and / or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate or sodium hydrogen carbonate. In order to accelerate the reaction, a catalyst such as dimethylaminopyridine may be added. Further, the compound (1e) may be used in excess in place of the organic base and / or the inorganic base. 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.

（式中、Xはハロゲン等の脱離基；Yは低級アルキル；nは１〜６の整数を示す。以下同様。）
本製造法は、式（Ｉ）で示される化合物のうち、Bがメチレン以外の低級アルキレンであり、R⁴とR⁵が架橋されておらず、R⁴とBが閉環していない化合物を製造する方法である。 (Second manufacturing method)

(In the formula, X represents a leaving group such as halogen; Y represents a lower alkyl; n represents an integer of 1 to 6. The same applies hereinafter.)
This production method produces a compound of formula (I) wherein B is lower alkylene other than methylene, R ⁴ and R ⁵ are not bridged, and R ⁴ and B are not ring-closed It is a method to do.

(Process A)
This step is a step for producing the compound (2c) by condensing the compound (2a) and the compound (2b). The method described in HAND, ES; JOHNSON, SC; BAKER, DC; J Org Chem 1997, 62 (5), 1348-1355.

(Process B)
This step is a step of constructing a thiazole ring by allowing thiourea to act after halogenating the α-position of the ketone of compound (2c). Vol. II, 1943, 31-32. Org. Syn. Coll. Vol. II, Maruzen Co., Ltd., 1992, “Fourth Edition Experimental Chemistry Lecture 19”, pages 431-435, or equivalent methods should be adopted. Can do.

(Process C)
In this step, the compound (2d) or the carboxylic acid body hydrolyzed as necessary is subjected to amidation according to the first production method step A, and then the amide bond is converted to aminomethylene by a reduction reaction. It is a process of converting into a bond. The method described in Maruzen Co., Ltd., 1992, “Fourth Edition, Experimental Chemistry Course 26”, pages 227-228, or a method analogous thereto can be employed.

(Process D)
This step is a step of producing compound (I) by amidating compound (1b) and compound (2e). It can carry out according to the 1st manufacturing method process A.

（式中、R¹²は前述の基を示す。以下同様。）
本製造法は、式（Ｉ）で示される化合物のうち、R⁴とR⁵がR¹¹により架橋されている化合物を製造する方法である。R¹¹がR⁵へ架橋するメチレンとして存在するのは、上記定義により、Bがメチレンであり、R⁴が式（ＩＩ）で示される基である場合である。 (3rd manufacturing method)

(In the formula, R ¹² represents the above-mentioned group. The same applies hereinafter.)
This production method is a method for producing a compound in which R ⁴ and R ⁵ are cross-linked by R ¹¹ among the compounds represented by the formula (I). R ¹¹ is present as methylene bridging to R ^{5 according} to the above definition when B is methylene and R ⁴ is a group of formula (II).

(Process A)
In this step, an aminomethyl group is introduced into the thiazole 5-position of the compound (1c) using a Mannich reaction using the compound (1c), and the iminium formed by the subsequent second stage Mannich reaction is represented by R ² . In this step, phenyl or thienyl is subjected to nucleophilic attack to give a tricyclic compound which is a compound relating to the active ingredient of the pharmaceutical composition of the present invention. It can carry out according to the 1st manufacturing method process B.

（式中、mは1〜6の整数を示す。以下同様。）
本製造法は、式（Ｉ）で示される化合物のうち、R⁴とBがR¹¹により閉環されている化合物を製造する方法である。R¹¹がBへ閉環する置換されていてもよい低級アルキレンとして存在するのは、上記定義により、Bがメチレンであり、R⁴が式（ＩＩ）で示される基である場合である。 (4th manufacturing method)

(In the formula, m represents an integer of 1 to 6. The same applies hereinafter.)
This production method is a method for producing a compound in which R ⁴ and B are closed by R ¹¹ among the compounds represented by the formula (I). R ¹¹ is present as optionally substituted lower alkylene ring-closing to B when, according to the above definition, B is methylene and R ⁴ is a group represented by formula (II).

(Process A)
This step can be performed according to the method of Van Tamelin, EE; Knapp, GC; J. Am. Chem. Soc., 77, 1860, 1955.

In the first production method to the fourth production method, the group represented by R ⁹ can be converted to R ⁶ at an appropriate time in the above-described step and proceed to the next step. As the conversion method, for example, in Step A, 5,6-dichloropyridin-3-yl or 3,4,5-difluorophenyl is introduced as R ^{9 at} an appropriate time, for example, in the first production method. Examples include a method of performing an ipso substitution by a nucleophilic substitution reaction before the step B, before the step C, or before the step D, and converting it to the partial structure R ⁶ of the compound according to the present invention.

  Furthermore, some compounds represented by the formula (I) can be generally employed by those skilled in the art such as known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, etc. from the compounds obtained as described above. It can also be produced by arbitrarily combining the steps.

The compound relating to the active ingredient of the pharmaceutical composition of the present invention produced as described above is isolated or purified as it is free or subjected to 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.

The pharmaceutical composition of the present invention comprises one or more compounds relating to the active ingredient of the pharmaceutical composition of the present invention represented by the formula (I), a pharmaceutical carrier, an excipient, and other additives usually used for formulation. It can be prepared by a commonly used method using an agent. 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 the solid composition for oral administration according to the present invention, 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, although an Example demonstrates this invention concretely, this invention is not restrict | limited at all by these Examples.

Example 1 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、本発明の医薬組成物がヒト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 pharmaceutical composition of the present invention has a Ba / F3 cell proliferation action via human c-Mpl.

Example 2 Measurement Test for Promoting Action of Megakaryocyte Colony Formation Human CD34 ⁺ cells rich in human hematopoietic progenitor cells were used with MegaCult ^™ -C (StemCell Technologies) in a 2-well chamber slide 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 compound relating to the active ingredient of the pharmaceutical composition of the present invention was 20 nM for the compound of Production Example 71, 34 nM for the compound of Production Example 100, 36 nM for the compound of Production Example 104, and Production Example The compound of 106 was 23 nM and the compound of Production Example 315 was 45 nM, and it was confirmed that the pharmaceutical composition of the present invention has an excellent megakaryocyte colony formation promoting action.

Example 3 Mouse Oral Administration Test Male ICR mice were orally administered 3 mg / kg or 10 mg / kg of the test compound dissolved or suspended in 0.5% aqueous methylcellulose solution (100 mg / kg in Comparative Compounds 1 to 3). 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 pharmaceutical composition of the present invention has oral activity in mice. In particular, in the case of the compound which is an active ingredient of the pharmaceutical composition of the present invention, the comparative compound showed almost no oral activity even in the “100 mg / kg-10% dilution conditions”, but the “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 conditions ''. This is considered to be achieved by introducing a lower alkylene having an amino group as a positional 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.).

Example 4 Platelet Increase Effect on Mice Recognized by Human Platelet Production Further, platelets were obtained by administering the pharmaceutical composition of the present invention to a mouse confirmed to produce human platelets after transplantation of human hematopoietic stem cells. It was confirmed that increased activity was observed.

Example 5 Production of a pharmaceutical composition for oral administration
20 g of the compound according to the active ingredient of the pharmaceutical composition of the invention is taken and mixed with 51 g of lactose and 21.8 g of corn starch. This mixture is granulated and dried with 20 g of an aqueous solution of 10% hydroxypropylcellulose (for example, trade name HPC-SL, manufactured by Shin-Etsu Chemical) using a fluidized bed granulator. 2 g of low-substituted hydroxypropylcellulose (for example, trade name L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) is mixed with the dried product, and further mixed with 0.2 g of magnesium stearate to obtain a mixed powder for tableting. This mixed powder is tableted using a rotary tableting machine (for example, manufactured by Kikusui Co., Ltd.), a tableting punch and a mortar having a diameter of 7 mm to obtain 100 mg tablets.

Example 6 Production of a pharmaceutical composition for parenteral administration
1 g of the compound according to the active ingredient of the pharmaceutical composition of the present invention is weighed and dissolved in 700 mL of water for injection. An additional 9 g of sodium chloride is dissolved in this solution. Adjust the pH to a predetermined value with a solution of hydrochloric acid / sodium hydroxide, and adjust the total volume to 1000 mL. Then, after aseptic filtration with a 0.2 μm filter, it is filled and sealed in an ampoule made of deborogenated borosilicate glass. Sterilization is performed in a high-pressure steam sterilizer under predetermined conditions to obtain an injection.

(Production example)
Hereinafter, the manufacture example of the compound which concerns on the active ingredient of the pharmaceutical composition of this invention is shown. In addition, the raw material compound used in a manufacture 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 manufacture example.

Reference production example 1
Potassium carbonate and allyl bromide were added to a DMF solution of 3,4,5-trifluorobenzoic acid and stirred overnight to obtain a crude allyl ester. Potassium carbonate was added to a DMF solution of crude allyl ester and ethyl isonipecotate, and the mixture was stirred overnight at room temperature to obtain a piperidine-substituted product. Morphine and tetrakis (triphenylphosphine) palladium (catalytic amount) were added to a THF solution of the piperidine-substituted product, and the mixture was stirred at 60 ° C. for 2 hours and at room temperature for 4 days. After distilling off the solvent, ether and EtOAc were added, washed with saturated aqueous sodium hydrogen carbonate solution 10 times, concentrated hydrochloric acid was added to the collected aqueous layer, and the resulting precipitate was collected by filtration to give 4- [4- (ethoxycarbonyl) Piperidin-1-yl] -3,5-difluorobenzoic acid was obtained.

Reference production example 2
To a DMF solution of 3-chloro-5-fluoro-4-hydroxybenzoic acid ethyl ester, potassium carbonate and 3- (tert-butyldimethylsilyloxy) propyl bromide were added, and the mixture was stirred at 50 ° C. 4- [3- (tert- Butyldimethylsilyloxy) propoxy] -3-chloro-5-fluorobenzoic acid ethyl ester was obtained.
In the same manner as in Reference Production Example 2, Reference Production Examples 3 to 4 shown in Table 3 were produced using the corresponding raw materials.

Reference production example 5
Piperazine anhydride was added to a THF solution of 3.4-difluorobenzoic acid methyl ester, and the mixture was stirred at 60 ° C. for 18 hours to obtain 3-fluoro-4-piperazin-1-ylbenzoic acid methyl ester.

Reference production example 6
Di-tert-butyl dicarbonate and 4-dimethylaminopyridine were added to a 1,2-dichloroethane solution of the compound of Reference Production Example 5, and the mixture was stirred at room temperature for 10 minutes to give 4- [2-fluoro-4- (methoxycarbonyl). Phenyl] piperazine-1-carboxylic acid tert-butyl ester was obtained.

Reference production example 7
N-chlorosuccinimide was added to the DMF solution of the compound of Reference Production Example 6, and the mixture was stirred at room temperature for 3 hours to give 4- [2-chloro-6-fluoro-4- (methoxycarbonyl) phenyl] piperazine-1-carboxylic acid tert -The butyl ester was obtained.

Reference production example 8
1M NaOH aqueous solution (aq) was added to a mixed solution of the compound of Reference Production Example 2 in MeOH-THF, stirred at room temperature for 16 hours, and 4- [3- (tert-butyldimethylsilyloxy) propoxy] -3-chloro- 5-Fluorobenzoic acid was obtained.
In the same manner as in Reference Production Example 8, Reference Production Examples 9 to 11 shown in Table 3 were produced using the corresponding raw materials.

Reference production example 12
Thionyl chloride was added to a MeOH solution of the compound of Reference Production Example 11, and the mixture was stirred at room temperature for 22 hours to obtain 4- [3- (methoxycarbonyl) propoxy] -3-fluorobenzoic acid.

The symbols in the table have the following meanings (the same applies hereinafter).
Rf: Reference production example number
Data: Physical data (MS: FAB-MS (M + H) ⁺ ; MN: FAB-MS (MH) ⁻ ; MM: FAB-MS (M) ⁺ ),
R, R ¹ , R ² , R ³ , R ⁴ , X, Y: Substituents in the general formula (Me: methyl, Et: ethyl, iPr: isopropyl, cPr: cyclopropyl, nBu: normal butyl, iBu: isobutyl , TBu: tertiary butyl, Ph: phenyl, Py: pyridyl, Boc: tert-butyloxycarbonyl, The: thienyl, azet: azetidin-1-yl, pyrr: pyrrolidin-1-yl, pipe: piperidin-1-yl , Pipa: piperazin-1-yl, mor: morpholin-4-yl, TBS: tertiary butyldimethylsilyl, di: di, the number before the substituent indicates the substitution position, and thus, for example, 3,5-diF- 4- (4-EtO ₂ C-pipe) Ph is 3,5-difluoro-4- (4-ethoxycarbonylpiperidin-1-yl) phenyl, 4-Me-2-The is 4-methylthiophene-2- Il)
Indicates.

Reference production example 13
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.
In the same manner as in Reference Production Example 13, Reference Production Example 14 shown in Table 4 was produced using the corresponding raw materials.

Reference production example 15
To a pyridine suspension of the compound of Reference Production Example 13, 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 then 5,6-dichloro-N— [4- (4-Chlorothiophen-2-yl) thiazol-2-yl] nicotinamide was obtained.
In the same manner as in Reference Production Example 15, Reference Production Examples 16 to 22 shown in Table 5 were produced using the corresponding raw materials.

Reference Production Example 23
To the compound of Reference Production Example 15, pyridine, triethylamine, and ethyl isonipecotate were added, and the mixture was stirred at 70 ° C. for 16 hours to give 1- (3-chloro-5-{[4- (4-chlorothiophen-2-yl) thiazole- 2-yl] carbamoyl} -2-pyridyl) piperidine-4-carboxylic acid ethyl ester was obtained.
In the same manner as in Reference Production Example 23, Reference Production Examples 24-31 shown in Table 6 were produced using the corresponding raw materials.

Reference Production Example 32
Acetic acid and an aqueous formaldehyde solution (36%) were added to the compound of Reference Production Example 23, and the mixture was stirred at 100 ° C. overnight. 1- (5-acetoxymethyl-4- (4-chlorothiophen-2-yl) thiazol-2-yl ) Carbamoyl) -3-chloro-2-pyridyl) piperidine-4-carboxylic acid ethyl ester was obtained.
In the same manner as in Reference Production Example 32, Reference Production Example 33 shown in Table 7 was produced using the corresponding raw materials.

  In the same manner as in Production Example 1 described later, Reference Production Examples 34 to 35 shown in Table 8 were produced using the corresponding raw materials.

Reference Production Example 36
To a chloroform-EtOH mixed solution of the compound of Reference Production Example 19 was added 4M HCl-EtOAc solution under ice cooling, and the mixture was stirred at room temperature for 17 hours, and then 3-chloro-N- [4- (4-chlorothiophen-2-yl) was stirred. ) Thiazol-2-yl] -5-fluoro-4-piperazin-1-ylbenzamide hydrochloride was obtained.

Reference Production Example 37
Potassium carbonate and ethyl bromoacetate were added to a DMF solution of the compound of Reference Production Example 36, and the mixture was stirred at room temperature for 23 hours. [4- (2-Chloro-4-{[4- (4-chlorothiophen-2-yl) Thiazol-2-yl] carbamoyl} -6-fluorophenyl) piperazin-1-yl] acetic acid ethyl ester was obtained.

Reference Production Example 38
To a pyridine suspension of 2-amino-4- [3- (trifluoromethyl) phenyl] thiazole and 5,6-dichloronicotinic acid, add phosphorus oxychloride at -30 ° C, gradually warm to room temperature, and overnight at room temperature Stir. After evaporating the solvent under reduced pressure, pyridine and EtOH were added, and the mixture was stirred at 50 ° C. for 30 min. Add triethylamine and ethyl isonipecotate at room temperature, stir at 80 ° C. for 15 hours, 1- [3-chloro-5-({4- [3- (trifluoromethyl) phenyl] thiazol-2-yl} carbamoyl)- 2-Pyridyl] piperidine-4-carboxylic acid ethyl ester was obtained.
In the same manner as in Reference Production Example 38, Reference Production Examples 39 to 40 shown in Table 10 were produced using the corresponding raw materials.

  In the same manner as in Reference Production Example 8, Reference Production Example 41 shown in Table 11 was produced, and in the same manner as in Production Example 8 described later, Reference Production Example 42 shown in Table 11 was produced using the corresponding raw materials. did.

Reference Production Example 43
To the THF solution of the compound of Reference Production Example 13, phenyl chloroformate and pyridine were added, and the mixture was stirred at room temperature for 1.5 hours. N- [4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamic acid The phenyl ester was obtained.

Reference Production Example 44
To a DMF solution of the compound of Reference Production Example 43, a mixture of N- (piperidin-4-yl) isonipecotic acid ethyl ester hydrochloride and N- (piperidin-4-yl) isonipecotic acid isopropyl ester hydrochloride, triethylamine was added, and 80 The mixture was stirred at 12 ° C. for 12 hours to obtain an ester mixture. Dissolve the ester mixture in MeOH, add triethylamine, sodium ethoxide, stir at room temperature to 50 ° C. for 18 hours, 1 ′-{[4- (4-chlorothiophen-2-yl) thiazol-2-yl] Carbamoyl} -1,4′-bipiperidine-4-carboxylic acid methyl ester was obtained.

Reference Production Example 45
4- (4-Chlorothiophen-2-yl) -4-oxobutanoic acid ester (methyl ester: ethyl ester 3: 2 mixture) was used as a starting material in the same manner as in Reference Production Example 13, and the reference production shown in Table 13 Example 45 was prepared.

Reference Production Example 46
In the same manner as in Reference Production Example 8, Reference Production Example 46 shown in Table 13 was produced using the corresponding raw materials.

Reference Production Example 47
To a DMF solution of the compound of Reference Production Example 46, butylmethylamine, WSC · HCl, HOBt, and triethylamine were added, and the mixture was stirred at room temperature for 18 hours. N-butyl-N-methyl- [2-amino-4- (4 -Chlorothiophen-2-yl) thiazol-5-yl] acetamide was obtained.

Reference production example 48
A THF solution of the compound of Reference Production Example 47 was added to a THF suspension of lithium aluminum hydride, and the mixture was stirred for 3 hours with heating under reflux to give 2-amino-5- {2- [butyl (methyl) amino] ethyl}- 4- (4-Chlorothiophen-2-yl) thiazole was obtained.

Reference Production Example 49
In the same manner as in Reference Production Example 15, Reference Production Example 49 shown in Table 13 was produced using the corresponding raw materials.

Reference production example 50
To a DMF solution of 2,6-dichloro-5-fluoronicotinic acid, add isonipecotic acid ethyl ester and stir at 80 ° C. to give 2-chloro-6- [4- (ethoxycarbonyl) piperidin-1-yl] -5 -Fluoronicotinic acid was obtained.

Reference Production Example 51
To a THF-EtOH solution of the compound of Reference Production Example 50, triethylamine and 10% palladium-supported carbon were added, 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.

  Reference Production Examples 52 to 53 shown in Table 15 in the same manner as Production Example 3 described later, Reference Production Examples 54 to 56 shown in Table 15 in the same manner as Reference Production Example 15, and Production Example 1 described later in the same manner Reference production examples 57 to 64 shown in Table 15 were produced using the corresponding raw materials.

Production Example 1
1- (3-Chloro-5-{[4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -2-pyridyl) piperidine-4-carboxylic acid ethyl ester 150 mg plus acetic acid 3 ml Then, 24 μl of formaldehyde aqueous 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. .

Production Example 2
1- (5-{[5-[(Acetoxy) methyl] -4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -3-chloro-2-pyridyl) piperidine-4-carvone N- (2-methoxyethyl) methylamine (39 μl), triethylamine (51 μl) and 4- (dimethylamino) pyridine (23 mg) were added to a suspension of acid ethyl ester (107 mg) in EtOH (6 ml), and the mixture was stirred at 50 ° C. for 2 hours. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate solution was added, extracted with EtOAc, and washed with water and saturated brine. After drying 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 (10: 1 to 3.5: 1) as an elution solvent, and 1- {3-chloro -5-[(4- (4-Chlorothiophen-2-yl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} piperidine- 90 mg of 4-carboxylic acid ethyl ester was obtained.

Production Example 3
1- [3-Chloro-5-({4- (4-chlorothiophen-2-yl) -5-[(cyclobutylamino) methyl] thiazol-2-yl} carbamoyl) -2-pyridyl] piperidine-4 -Carboxylic acid ethyl ester 79 mg 1.2-dichloroethane 2 ml was added with 35% formalin 110 μl and acetic acid 76 μl and stirred at room temperature for 1 hour, then NaBH (OAc) ₃ 45 mg was added and stirred at room temperature for 1 hour. Chloroform was added to the reaction solution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: EtOAc = 4: 1 to 2: 1) and 58 mg of 1- {3-chloro-5-[(4- (4-chlorothiophene). -2-yl) -5-{[cyclobutyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} piperidine-4-carboxylic acid ethyl ester was obtained.

Production Example 4
5,6-dichloro-N- [4- (4-chlorothiophen-2-yl) -5- (piperidin-1-ylmethyl) -1,3-thiazol-2-yl] nicotinamide 413 mg THF 5 ml To the solution, 1.3 ml of ethyl isonipecotate was added and stirred for 5 days. After evaporating the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the resulting precipitate was collected by filtration. This was dissolved in chloroform, 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 (4: 1 to 3: 1) as an elution solvent, and 1- (3-chloro-5-{[4 There was obtained 468 mg of-(4-chlorothiophen-2-yl) -5- (piperidinomethyl) thiazol-2-yl] carbamoyl} -2-pyridyl) piperidine-4-carboxylic acid ethyl ester.

Production Example 5
1- {3-chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} thiazol-2-yl) carbamoyl]- To a suspension of 76 mg of 2-pyridyl} piperidine-4-carboxylic acid ethyl ester in 1.5 ml of EtOH was added 0.4 ml of 1M aqueous sodium hydroxide solution, and the mixture was stirred at 60 ° C. for 2 hours. At room temperature, 0.6 ml of 1M hydrochloric acid and 0.5 ml of water were added, and the resulting precipitate was collected by filtration and washed with 50% aqueous ethanol. 1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2-methoxyethyl) (methyl) amino] methyl} thiazole-2- Yl) carbamoyl] -2-pyridyl} piperidine-4-carboxylic acid hydrochloride 73 mg was obtained.

Production Example 6
Ethyl [4- (5-{[5-{[Butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -3-chloro-2-pyridyl 19 mg of sodium borohydride was added to a solution of 128 mg of 2-oxopiperazin-1-yl] acetate in 5 ml of THF and refluxed with stirring. A solution obtained by dissolving 128 mg of MeOH in 2 ml of THF was slowly added dropwise thereto, and then stirred under reflux for 1 hour. The reaction mixture was ice-cooled, water was added, the mixture was extracted with chloroform, washed with saturated brine, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography using chloroform: MeOH (99: 1 to 98: 2) as an elution solvent. The obtained crude product was suspended in methanol, insoluble matter was removed by filtration, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in EtOAc, 4M HCl-EtOAc solution was added and stirred, and then the resulting precipitate was collected by filtration, dried under reduced pressure, and N- [5-{[butyl (methyl) amino] methyl}- 4- (4-Chlorothiophen-2-yl) thiazol-2-yl] -5-chloro-6- [4- (2-hydroxyethyl) -3-oxopiperazin-1-yl] nicotinamide hydrochloride 15 mg Got.

Production Example 7
40 mg of the compound of Production Example 132 was dissolved in 6 ml of MeOH, 1.6 ml of concentrated hydrochloric acid was added and stirred for 2 hours. After concentration, the precipitate was filtered, washed with EtOAc, and 32 mg of N- [5-{[ Butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -4- (2-hydroxymethoxy) -3-methoxybenzamide hydrochloride was obtained.

Production Example 8
1- {3-chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(3-methoxypropyl) (methyl) amino] methyl} thiazol-2-yl) carbamoyl]- 2-Pyridyl} piperidine-4-carboxylic acid hydrochloride (52 mg) in 2 ml of a THF solution was added triethylamine (30 μl), morpholine (30 μl), WSC / HCl (45 mg), and HOBt (30 mg), and the mixture was stirred overnight at room temperature. Chloroform was added to the reaction solution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: chloroform: MeOH = 100: 1-50: 1, hexane: EtOAc = 2: 1, then chloroform: MeOH = 20: 1) Suspend in 2 ml of diethyl ether, add 2 ml of 4 N HCl-EtOAc, collect the precipitate by filtration, 25 mg of 5-chloro-N- (4- (4-chlorothiophen-2-yl) -5- { [(3-Methoxypropyl) (methyl) amino] methyl} thiazol-2-yl) -6- [4- (morpholinocarbonyl) piperidino] nicotinamide hydrochloride was obtained.

Production Example 9
To 188 mg of the compound of Production Example 190, 3 ml of 4M HCl-dioxane solution was added, followed by heating and stirring at 50 ° C. for 18 hours. After cooling the reaction solution at room temperature, the precipitated solid was filtered to give 160 mg of [(1- {3-chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2 -Methoxyethyl) (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} -4-piperidyl) oxy] acetic acid hydrochloride was obtained.

Production Example 10
200 mg of the compound of Reference Production Example 23 was dissolved in 5 ml of formic acid, 37 μl of methoxyethylamine and 92 μl of 35% formalin were added and stirred at 70 ° C. for 15 hours. The reaction mixture was concentrated, chloroform was added, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: EtOAc = 5: 1-3: 1) and 110 mg of 1- {3-chloro-5-{[7-chloro-5- ( 2-methoxyethyl) -5,6-dihydro-4H-thiazolo [5,4-c] thieno [2,3-e] azepin-2-yl] carbamoyl} -2-pyridine} -4-carboxylic acid ethyl ester Got.

Production Example 11
6-[(2-Aminoethyl) amino] -N- [5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloro Nicotinamide trihydrochloride (100 mg) was suspended in THF (5 ml), triethylamine (85 μl) was added, and the mixture was cooled to 0 ° C. 13 μl of methanesulfonyl chloride was added to the solution and stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with chloroform, the organic layer was washed with water and brine, and then dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: MeOH = 10: 1) and 75 mg of N- [5-{[butyl (methyl) amino] methyl} -4- (4-chloro Thiophen-2-yl) thiazol-2-yl] -5-chloro-6-({2-[(methylsulfonyl) amino] ethyl} amino) nicotinamide was obtained.

Tables 16 to 31 below show the structures and physical data of the production example compounds. The symbols in the table have the following meanings (the same applies hereinafter).
Ex: Production Example Number (If only a number is written in the Ex column, it indicates that the compound of the Production Example Number is a free form, followed by a slash (/) and "HCl" following the number. In this case, it indicates that the compound of the production example number is hydrochloride)
Syn: production method (numbers indicate synthesis using corresponding raw materials in the same manner as production example compounds having the number as a production example number),
R: a substituent in the general formula (nPr: normal propyl, cBu: cyclobutyl, cHex: cyclohexyl, MOM: methoxymethyl, Ac: acetyl, Ms: methanesulfonyl, THF: tetrahydrofuryl, THP: tetrahydropyranyl).

Tables 32 to 34 below show the NMR data of some of the compounds of the production examples. 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 (9)

A pharmaceutical composition comprising a 2-acylaminothiazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[The symbols in the formula have the following meanings.
B: Lower alkylene.
R ⁴ : a group represented by the formula (II), or an optionally substituted cyclic amino.

[The symbols in the formula have the following meanings.
R ¹¹ : H, optionally substituted lower alkyl, or optionally substituted cycloalkyl. When B represents methylene, R ¹¹ may exist as methylene that bridges to thienyl or phenyl represented by R ⁵ . Further, when B represents methylene, R ¹¹ may be present as an optionally substituted lower alkylene that cyclizes to the methylene represented by B.
R ¹² : lower alkyl, cycloalkyl or non-aromatic heterocycle, each optionally substituted. ]
R ⁵ : each optionally substituted thienyl or phenyl.
R ⁶ : Aromatic hetero ring, aryl or cyclic amino, each optionally substituted. However, unsubstituted phenyl and indole which may be substituted are excluded. ] The pharmaceutical composition according to claim 1, wherein B is methylene. The R ⁵ is lower alkyl optionally substituted with one or more halogens, and thienyl or phenyl each substituted with one or more groups selected from the group consisting of halogens. Pharmaceutical composition. The pharmaceutical composition according to claim 3, wherein R ⁶ is optionally substituted pyridyl, or substituted phenyl. R ⁶ is pyridin-3-yl substituted at the 5-position with a group selected from the group consisting of chloro and fluoro, and further substituted at the 6-position, or a group selected from the group consisting of chloro and fluoro The pharmaceutical composition according to claim 4, which is phenyl substituted at the position and substituted at the 5-position with a group selected from the group consisting of -H, chloro and fluoro, and further substituted at the 4-position. Among the pharmaceutical compositions according to claim 1,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[cyclobutyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} piperidine -4-carboxylic acid,
1- (5-{[5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] carbamoyl} -3-chloro-2-pyridyl) piperidine -4-carboxylic acid,
1- {5-[(4- (4-Chlorothiophen-2-yl) -5-{[(2R) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl] -3- Fluoro-2-pyridyl} piperidine-4-carboxylic acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(2S) -2-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl ] -2-pyridyl} piperidine-4-carboxylic acid,
1- (3-Chloro-5-{[4- (4-chlorothiophen-2-yl) -5- (dimethylaminomethyl) thiazol-2-yl] carbamoyl} -2-pyridyl) piperidine-4-carboxylic acid ,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[isopropyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} piperidine -4-carboxylic acid,
4-[{3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[isopropyl (methyl) amino] methyl} thiazol-2-yl) carbamoyl] -2-pyridyl} (Methyl) amino] butyric acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[(3S) -3-methylpyrrolidin-1-yl] methyl} thiazol-2-yl) carbamoyl ] -2-pyridyl} piperidine-4-carboxylic acid,
1- {3-Chloro-5-[(4- (4-chlorothiophen-2-yl) -5-{[[(2S) -2-methoxypropyl] (methyl) amino] methyl} thiazol-2-yl ) Carbamoyl] -2-pyridyl} piperidine-4-carboxylic acid,
N- [5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloro-6-[(3-hydroxypropyl) amino] Nicotinamide,
N- [5-{[butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloro-6- (3-oxopiperazin-1-yl ) Nicotinamide, or
N- [5-{[Butyl (methyl) amino] methyl} -4- (4-chlorothiophen-2-yl) thiazol-2-yl] -5-chloro-6- [4- (hydroxymethyl) piperidino] Nicotinamide,
Or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to any one of claims 1 to 6, which is a platelet increasing agent. The pharmaceutical composition according to any one of claims 1 to 6, which is a therapeutic agent for thrombocytopenia. The pharmaceutical composition according to any one of claims 1 to 6, which is a c-Mpl ligand.