JP4317818B2 - Novel salt of 2-acylaminothiazole derivative - Google Patents
Novel salt of 2-acylaminothiazole derivative Download PDFInfo
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- JP4317818B2 JP4317818B2 JP2004539569A JP2004539569A JP4317818B2 JP 4317818 B2 JP4317818 B2 JP 4317818B2 JP 2004539569 A JP2004539569 A JP 2004539569A JP 2004539569 A JP2004539569 A JP 2004539569A JP 4317818 B2 JP4317818 B2 JP 4317818B2
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- Health & Medical Sciences (AREA)
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- Medicinal Chemistry (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本発明は、医薬、殊に血小板減少症治療剤として有用な1−(3−クロロ−5−{[4−(4−クロロチオフェン−2−イル)−5−(4−シクロヘキシルピペラジン−1−イル)チアゾール−2−イル]カルバモイル}ピリジン−2−イル)ピペリジン−4−カルボン酸 マレイン酸塩(以下、「化合物A」と言う。)及び化合物Aを有効成分とする医薬に関する。 The present invention relates to 1- (3-chloro-5-{[4- (4-chlorothiophen-2-yl) -5- (4-cyclohexylpiperazine-1-), which is useful as a medicament, particularly a therapeutic agent for thrombocytopenia. Yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleate (hereinafter referred to as “compound A”) and a pharmaceutical comprising compound A as active ingredients.
血小板は生理的止血および病的血栓形成に主要な働きを果たす無核の血球細胞であり、生体内において、血小板は前駆細胞である巨核球から絶えず産生される。血小板産生は他の血球と同様に多能性幹細胞に由来し、多能性幹細胞は巨核球系の前駆細胞になり、それから巨核芽球、前巨核球、巨核球になる。この巨核球の成熟の過程において未熟な巨核球は細胞分裂を伴わずにDNA合成だけを行って多倍数体となる。その後、細胞質の成熟が始まり、血小板分離膜が形成され、細胞質が断裂して血小板が放出される。
一方、再生不良性貧血、骨髄異形成症候群、又は悪性腫瘍の化学療法、放射線療法等における種々の造血障害による血小板の減少は出血傾向を招く等の重篤な症状を引き起こすため、それらの治療を目的に血小板を増多させる様々な技術の開発の試みが行われてきた。現在、血小板減少症治療の有力な手段は血小板輸血であるが、十分量の血小板が供給されている状況ではなく、また、移入した血小板の寿命が短い等の理由により、血小板減少症を十分に改善することは困難である。さらに、血小板輸血にはウイルス感染、同種抗体の産生、移植細胞対宿主病(Graft Versus Host Disease:GVHD)等の問題点がある。このため、種々の症状あるいは治療によって引き起こされる造血機能の抑制状態を緩和し、血小板数の回復を促進させる薬剤の開発が期待されている。
そのような中、巨核球系細胞への分化に関与する主要な因子であり、c−Mplリガンドであるトロンボポエチン(以下、「TPO」と言う。)がクローニングされ、巨核球系細胞の分化及び/又は増殖を刺激して血小板産生を促進することが報告された(非特許文献1)。TPOはすでに血小板増多剤として臨床試験が行われており、ヒトでの有用性と忍容性が確認されつつある。しかし、TPOの一種であるPEG−rHuMGDF(TPOのN末端から163番目のアミノ酸がポリエチレングリコールで修飾されたもの)の臨床試験において、中和抗体が確認された(非特許文献2、非特許文献3)ため、TPOの免疫原性が懸念されている。また、TPOは蛋白質であるため、消化管内で分解されてしまい、経口投与薬剤としては実用的ではない。同様の理由で低分子ペプチドも経口投与薬剤としては実用的ではないと考えられる。このような状況下、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リガンドの開発が進められている。
上記のような化合物としては、ベンゾジアゼピン誘導体(特許文献1)、アシルヒドラゾン誘導体(特許文献2)、ジアゾナフタレン誘導体(特許文献3)、ピロロカルバゾール誘導体(特許文献4)、ピロロフェナンスリジン誘導体(特許文献5)、ピロロフタルイミド誘導体(特許文献6)が知られている。
また、下記一般式(I)で示される化合物が血小板増多作用を有することが知られている(特許文献7)。
(式中の記号は、該公報参照)
特許文献7においては、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、本発明化合物においては、チアゾリル基のごとき当該文献におけるA1基を有さない。しかも、当該文献においては、チアゾール5位に窒素原子が直接置換し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。
また、下記一般式(II)で示される化合物が血小板増多作用を有することが知られている(特許文献8)。
(式中の記号は、該公報参照)
特許文献8においては、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、本発明化合物においては、当該文献におけるW1基を有さない。しかも、当該文献においては、チアゾール5位に窒素原子が直接置換し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。
また、下記一般式(III)で示される化合物が血小板増多作用を有することが知られている(特許文献9)。
(式中の記号は、該公報参照)
特許文献9においては、R1がそれぞれ置換されていてもよいアリール若しくはピリジルの化合物が開示されているが、本発明化合物のごとき置換されたチエニルの化合物は開示されていない。また、Arとして置換基を有していてもよいピリジルの化合物が開示されているが、本発明のごとき置換されたピペリジン環を置換基として有するピリジルの化合物は開示されていない。
また、上記の他に、チアゾール5位に窒素原子が直接置換した2−アシルアミノチアゾール化合物として、コレシストキニン及びガストリン受容体拮抗作用を有する化合物(特許文献10)、及び抗炎症特性を有する化合物(非特許文献4)が知られているが、いずれも本発明にかかる血小板増多作用については知られていない。
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。
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. Further, platelet transfusion has problems such as viral infection, production of alloantibodies, and grafted cell 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 (hereinafter referred to as “TPO”), which is a major factor involved in differentiation into megakaryocyte cells and is a c-Mpl ligand, has been cloned to differentiate and / or differentiate megakaryocyte cells. Alternatively, it has been reported that stimulation of proliferation promotes platelet production (Non-patent Document 1). 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 kind of TPO (the amino acid at which the 163rd amino acid from the N-terminus of TPO is modified with polyethylene glycol), a neutralizing antibody was confirmed (Non-patent document 2, Non-patent document). 3) Therefore, 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 a drug for oral administration. 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.
Moreover, it is known that the compound represented by the following general formula (I) has a platelet-increasing action (Patent Document 7).
(Refer to this publication for symbols in the formula)
Patent Document 7 describes a compound containing thiazole which may be substituted as X 1 and -NHCO- as Y 1 . However, the compound of the present invention does not have the A 1 group in the literature such as thiazolyl group. In addition, in this document, there is no specific disclosure of the compounds in which the nitrogen atom is directly substituted at the 5-position of thiazole by Examples and others.
Further, it is known that a compound represented by the following general formula (II) has a platelet-increasing action (Patent Document 8).
(Refer to this publication for symbols in the formula)
Patent Document 8 describes a thiazole which may be substituted as X 1 and a compound containing —NHCO— as Y 1 . However, the compound of the present invention does not have the W 1 group in this document. In addition, in this document, there is no specific disclosure of the compounds in which the nitrogen atom is directly substituted at the 5-position of thiazole by Examples and others.
Further, it is known that a compound represented by the following general formula (III) has a platelet-increasing action (Patent Document 9).
(Refer to this publication for symbols in the formula)
Patent Document 9 discloses aryl or pyridyl compounds in which R 1 may be substituted, but does not disclose substituted thienyl compounds such as the compounds of the present invention. Moreover, although the pyridyl compound which may have a substituent as Ar is disclosed, the pyridyl compound which has the piperidine ring substituted like the present invention as a substituent is not disclosed.
In addition to the above, as a 2-acylaminothiazole compound in which a nitrogen atom is directly substituted at the 5-position of thiazole, a compound having a cholecystokinin and gastrin receptor antagonistic activity (Patent Document 10), and a compound having anti-inflammatory properties (Non-Patent Document 4) is known, but none of them is known about the platelet increasing action according to 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.
本発明者等は、血小板増多作用を有する化合物について鋭意研究し、2−アシルアミノチアゾール誘導体の新規な塩、即ち化合物Aが優れた血小板増多作用を有することを見いだし、本発明を完成させたものである。
本発明化合物である化合物Aは以下の化学構造を有する。
即ち、本発明によれば血小板増多剤として有用な化合物A、並びに、化合物Aを有効成分とする医薬、特に血小板増多剤及び/又は血小板減少症治療剤が提供される。
なお、本発明化合物は水和物及び/又は溶媒和物を形成する場合があるが、これらの化合物も本発明に包含される。
(製造法)
本発明化合物は、その基本骨格あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。以下に代表的な製法を例示する。また、各工程はそれらの順番を入れ替えて行うことができる場合がある。なお、官能基の種類によっては、当該官能基を原料ないし中間体の段階で適当な保護基、すなわち容易に当該官能基に転化可能な基に置き換えておくことが製造技術上効果的な場合がある。しかるのち、必要に応じて保護基を除去し、所望の化合物を得ることができる。このような官能基としては例えばカルボキシル基やアミノ基等を挙げることができ、それらの保護基としては例えばグリーン(Greene)及びウッツ(Wuts)著、「Protective Groups in Organic Synthesis(third edition)」に記載の保護基を挙げることができ、これらを反応条件に応じて適宜用いればよい。
本製法は、化合物(1a)に対し、チオ尿素を用いた環化反応を行い(工程1)、得られた化合物(1b)のチアゾール5位にシクロヘキシルピペラジノ基を導入し(工程2)、得られた化合物(1c)とジクロロニコチン酸とのアミド化反応(工程3)により得られる化合物(1d)にピペリジンカルボン酸又はその保護体を結合させ、必要により脱保護の後、通常の造塩反応を施して(工程4)、本発明化合物を製造する方法である。
工程1は、化合物(1a)のカルボニルα位のハロゲン化、代表的には臭素、N−ブロモコハク酸イミド等のブロム化剤を用いたブロモ化の後、チオ尿素を用いて環化反応を行い、チアゾール環を構築する工程である。ハロゲン化に用いられるハロゲン化剤としては、カルボニルα位のハロゲン化反応に通常用いられるハロゲン化剤であればいずれでもよく、N−ブロモコハク酸イミドやN−クロロコハク酸イミド等のイミド系ハロゲン化剤、ジオキサンジブロミド、フェニルトリメチルアンモニウムトリブロミド、ピリジニウムヒドロブロミドペルブロミド、ピロリドンヒドロトリブロミド等のピリジン、α−ピロリドン、4級アンモニウム、ジオキサン等の過臭化物等が好適に用いられるが、塩素、臭素などのハロゲン単体や、塩化水素、臭化水素等のハロゲン化水素酸、臭化銅(II)、塩化銅(II)等のハロゲン化銅(II)等の金属試薬を用いることもできる。
反応はハロゲン化炭化水素類、エーテル類、アルコール類、芳香族炭化水素類、酢酸、エステル類などの反応に不活性な有機溶媒中行われ、反応温度は−30℃乃至使用する溶媒の還流温度で行うのが好ましい。
チアゾールの環化反応では、反応に不活性な溶媒、好適には、エタノール、2−プロパノール等のアルコール類中、冷却下、冷却乃至室温下あるいは室温乃至加熱下において行われる。
工程2は、化合物(1b)のチアゾール5位のハロゲン化、代表的にはN−ブロモコハク酸イミド等のブロム化剤を用いたブロモ化の後、シクロヘキシルピペラジンによる置換反応を行い、シクロヘキシルピペラジノ基を導入する工程である。ハロゲン化反応は、工程1のハロゲン化反応に準じて行うことができ、置換反応は、反応に不活性な溶媒(テトラヒドロフラン等のエーテル類、及び、N,N−ジメチルホルムアミド、N−メチルピロリドン等の非プロトン性極性溶媒が好適に用いられる。)中、冷却下、冷却下乃至室温下、若しくは、室温下乃至加熱下において行われる。なお、置換反応に際して、どちらかの化合物を過剰に用いたり、N−メチルモルホリン、トリメチルアミン、トリエチルアミン、N,N−ジメチルアニリン、ピリジン、4−(N,N−ジメチルアミノ)ピリジン、ピコリン、ルチジンなどの塩基の存在下に反応させるのが、反応を円滑に進行させる上で有利な場合がある。
工程3は、化合物(1c)とジクロロニコチン酸とをアミド化反応により縮合する工程であり、ジクロロニコチン酸はその反応性誘導体を用いることもできる。そのような反応性誘導体としては、酸クロライド、酸ブロマイド等の酸ハライド;酸アジド;N−ヒドロキシベンゾトリアゾール、p−ニトロフェノールやN−ヒドロキシスクシンイミド等との活性エステル;対称型酸無水物;アルキル炭酸、p−トルエンスルホン酸などとの混合酸無水物等が挙げられる。好適には反応系中において(in situ)、オキシ塩化リン、シュウ酸クロリド、塩化チオニル等のクロロ化剤を用いて酸クロライドを発生させ、化合物(1c)を作用させて縮合を行う方法が挙げられる。また、ジクロロニコチン酸を遊離酸で反応させるとき、あるいは活性エステルや酸ハライドを単離せずに反応させるときなどは、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール、ジフェニルホスホリルアジド、ジエチルホスホリルシアニドや1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩などの縮合剤、ピリジン溶媒中オキシ塩化リンを用いて反応させるのが好適である。
反応は使用する反応性誘導体や縮合剤によっても異なるが、通常ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、エステル類、アセトニトリル、N,N−ジメチルホルムアミドやジメチルスルホキシド等の反応に不活性な有機溶媒中、冷却下、冷却乃至室温下あるいは室温乃至加熱下に行われる。
工程4は、化合物(1d)のピリジン6位のクロロ基をピペリジンカルボン酸又はその保護体で置換した後、必要に応じてカルボン酸へと誘導し、マレイン酸を用いて造塩反応を行い、本発明化合物を製造する工程である。ピペリジンカルボン酸又はその保護体による置換反応は工程2の置換反応に準じて行うことができ、必要なカルボン酸への誘導及び造塩反応は当業者にとって自明の方法又はそれに準じた方法を適用することができる。
このようにして製造された本発明化合物は、抽出、濃縮、留去、結晶化、濾過、再結晶、各種クロマトグラフィー等の通常の化学操作を適用して単離・精製される。The present inventors diligently researched on a compound having a platelet-increasing action, and found that a novel salt of a 2-acylaminothiazole derivative, that is, Compound A has an excellent platelet-increasing action, thereby completing the present invention. It is a thing.
Compound A which is the compound of the present invention has the following chemical structure.
That is, according to the present invention, there are provided Compound A useful as a platelet-increasing agent, and a medicament containing Compound A as an active ingredient, particularly a platelet-increasing agent and / or a therapeutic agent for thrombocytopenia.
In addition, although this invention compound may form a hydrate and / or a solvate, these compounds are also included by this invention.
(Production method)
The compound of the present invention can be produced by applying various known synthesis methods utilizing characteristics based on the basic skeleton or the type of substituent. The typical production method is illustrated below. In addition, there are cases where each step can be performed by changing their order. 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 a functional group include a carboxyl group and an amino group, and examples of protective groups thereof include those described in “Protective Groups in Organic Synthesis (third edition)” by Green and Wuts. The protecting groups described can be mentioned, and these may be used as appropriate according to the reaction conditions.
In this production method, cyclization reaction using thiourea is performed on the compound (1a) (step 1), and a cyclohexylpiperazino group is introduced into the 5-position of thiazole of the obtained compound (1b) (step 2). Then, piperidinecarboxylic acid or a protected form thereof is bound to the compound (1d) obtained by the amidation reaction of the obtained compound (1c) and dichloronicotinic acid (step 3), and after deprotection, if necessary This is a method for producing a compound of the present invention by subjecting it to a salt reaction (Step 4).
The reaction is carried out in an organic solvent inert to the reaction such as halogenated hydrocarbons, ethers, alcohols, aromatic hydrocarbons, acetic acid, esters, etc., and the reaction temperature is from −30 ° C. to the reflux temperature of the solvent used. It is preferred to do so.
The cyclization reaction of thiazole is performed in a solvent inert to the reaction, preferably an alcohol such as ethanol or 2-propanol, under cooling, cooling to room temperature, or room temperature to heating.
Step 2 includes halogenation of thiazole 5-position of compound (1b), typically bromination using a brominating agent such as N-bromosuccinimide, followed by substitution reaction with cyclohexylpiperazine, and cyclohexylpiperazino. This is a step of introducing a group. The halogenation reaction can be carried out according to the halogenation reaction in
Step 3 is a step of condensing compound (1c) and dichloronicotinic acid by an amidation reaction, and dichloronicotinic acid may be a reactive derivative thereof. Examples of such reactive derivatives include acid halides such as acid chloride and acid bromide; acid azides; active esters with N-hydroxybenzotriazole, p-nitrophenol, N-hydroxysuccinimide, and the like; symmetrical acid anhydrides; Examples thereof include mixed acid anhydrides such as carbonic acid and p-toluenesulfonic acid. Preferably, in the reaction system (in situ), an acid chloride is generated using a chlorinating agent such as phosphorus oxychloride, oxalic chloride, thionyl chloride, etc., and the condensation is performed by reacting compound (1c). It is done. When reacting dichloronicotinic acid with a free acid or reacting without isolating an active ester or acid halide, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl cyanide, 1-ethyl- The reaction is preferably carried out using a condensing agent such as 3- (3-dimethylaminopropyl) carbodiimide hydrochloride and phosphorus oxychloride in a pyridine solvent.
Although the reaction varies depending on the reactive derivative and condensing agent used, it is generally not suitable for reactions such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and the like. The reaction is carried out in an active organic solvent under cooling, cooling to room temperature, or room temperature to heating.
Step 4 replaces the chloro group at the 6-position of pyridine of the compound (1d) with piperidinecarboxylic acid or a protected form thereof, and then leads to carboxylic acid as necessary, and performs a salt formation reaction using maleic acid, This is a process for producing the compound of the present invention. The substitution reaction with piperidinecarboxylic acid or its protected form can be carried out in accordance with the substitution reaction in Step 2, and the derivatization to the necessary carboxylic acid and the salt formation reaction are carried out by a method obvious to those skilled in the art or a method analogous thereto. be able to.
The compound of the present invention thus produced is isolated and purified by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatographies and the like.
本発明化合物は優れた血小板増多作用を有する。
従って、本発明化合物は再生不良性貧血、骨髄異形成症候群における血小板減少症、悪性腫瘍の化学療法や放射線療法による血小板減少症、特発性血小板減少性紫斑病、肝疾患における血小板減少症、HIVによる血小板減少症等、種々の血小板減少症の治療及び/又は予防に有用であり、また、化学療法や放射線療法により血小板減少が生じる可能性がある場合、それらの療法を施す前にあらかじめ投与しておくこともできる。また、本発明化合物は経口剤として使用する際に十分な経口吸収性を有する。
本発明化合物の薬理作用は以下の試験により確認された。
(1)ヒトc−mpl−Ba/F3細胞の細胞増殖試験
96ウェルマイクロプレートに、2×105cells/mlのヒトc−mpl−Ba/F3細胞を、各濃度の被験化合物を添加した10%牛胎児血清含有RPMI1640培地(100μl/ウェル)にて37℃で培養した。培養開始24時間後にWST−1/1−methoxy PMS(細胞計測キット,同仁)の10μl/ウェルを添加した。添加直後及び2時間後にA450/A650の吸光度をマイクロプレートリーダー(Model3350:Bio−Rad)にて測定し、2時間での吸光度の増加を各被験化合物の増殖活性とした。その結果を表1に示す。
なお、表中の語句は以下の意味を示す。
Efficacy:rhTPOの最大細胞増殖活性値を100%としたときの被験化合物の最大細胞増殖活性値。
表中、比較化合物とは、特許文献9記載の実施例2の化合物であり、以下の構造を有する。
また、c−Mplを導入していないBa/F3細胞を用いた場合には、いずれも細胞増殖作用を示さなかった。以上の結果より、化合物A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。
(2)マウス経口投与試験
雄性ICRマウスに、0.5%メチルセルロース水溶液にて懸濁させた被験化合物3mg/kgを経口投与した。投与2時間後に、腹部下大静脈より1/10容3.8%クエン酸ナトリウムを抗凝固剤として採血した。12,000rpmで3分間遠心分離して得られた血漿を56℃で30分間加温したものを(1)記載のヒトc−mpl−Ba/F3細胞増殖試験の系に最終濃度0.3%血漿になるように添加し、細胞増殖活性を測定し、各被験化合物の最大の細胞増殖活性を100%としたときの各血漿の細胞増殖活性(%)を求めた。その結果を表2に示す。
上記の結果より、本発明化合物がマウスにて経口活性を有することが確認された。
本発明の医薬は、本発明化合物と通常製剤化に用いられる、薬剤用単体、賦形剤、その他添加剤を用いて、通常使用されている方法によって調製することができる。投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、静注、筋注等の注射剤、又は座剤、経鼻、経粘膜、経皮などによる非経口投与のいずれの形態であってもよい。
本発明による経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、本発明化合物が少なくとも1種の不活性な希釈剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な希釈剤以外の添加剤、例えばステアリン酸マグネシウム等の潤滑剤、繊維素グリコール酸カルシウム等の崩壊剤、ラクトース等の安定化剤、グルタミン酸又はアスパラギン酸等の溶解補助剤等を含有していてもよい。錠剤又は丸剤は必要によりショ糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート等の糖衣又は胃溶性若しくは腸溶性のフィルムで被覆してもよい。
経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤、エリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水、エタノール(EtOH)を含む。この組成物は不活性な希釈剤以外に湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。
非経口投与のための注射剤としては、無菌の水性又は非水性の溶液剤、懸濁剤、乳濁剤を含有する。水性の溶液剤、懸濁剤としては、例えば注射用蒸留水及び生理食塩水が含まれる。非水性の溶液剤、懸濁剤としては、例えばプロピレングリコール、ポリエチレングリコール、オリーブ油等の植物油、EtOH等のアルコール類、ポリソルベート80等がある。このような組成物は、さらに防腐剤、湿潤剤、乳化剤、分散剤、例えばラクトース等の安定剤、例えばグルタミン酸やアスパラギン酸のような溶解補助剤等の補助剤を含んでいてもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。これらはまた無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解して使用することもできる。
通常経口投与の場合、1日の投与量は、体重あたり約0.0001〜50mg/kg、好ましくは約0.001〜10mg/kgが適当で、さらに好ましくは0.01〜1mg/kgが適当であり、これを1回で又は2乃至4回に分けて投与する。静脈投与される場合は、1日の投与量は体重あたり約0.0001〜1mg/kg、好ましくは約0.0001〜0.1mg/kgが適当で、1日1回乃至複数回に分けて投与する。投与量は症状、年齢、性別等を考慮して個々の場合に応じて適宜決定される。The compound of the present invention has an excellent platelet-increasing action.
Therefore, the compound of the present invention is aplastic anemia, thrombocytopenia in myelodysplastic syndrome, thrombocytopenia caused by chemotherapy or radiotherapy of malignant tumor, idiopathic thrombocytopenic purpura, thrombocytopenia in liver disease, 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 compound of the present invention has sufficient oral absorbability when used as an oral preparation.
The pharmacological action of the compound of the present invention was confirmed by the following test.
(1) Cell proliferation test of human c-mpl-Ba / F3 cells 2 × 10 5 cells / ml of human c-mpl-Ba / F3 cells were added to a 96-well microplate 10 The cells were cultured at 37 ° C. in RPMI 1640 medium (100 μl / well) containing% fetal bovine serum. Twenty-four hours after the start of the culture, 10 μl / well of WST-1 / 1-methoxy PMS (Cell Counting Kit, Dojin) was added. Immediately after the 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 terms in the table have the following meanings.
Efficacy: the maximum cell growth activity value of the test compound when the maximum cell growth activity value of rhTPO is 100%.
In the table, the comparative compound is the compound of Example 2 described in Patent Document 9 and has the following structure.
Further, when Ba / F3 cells into which c-Mpl had not been introduced were used, none of them exhibited cell proliferation action. From the above results, it was confirmed that Compound A has a Ba / F3 cell proliferation action via human c-Mpl.
(2) Mouse Oral Administration Test 3 mg / kg of the test compound suspended in a 0.5% aqueous methylcellulose solution was orally administered to male ICR mice. 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 the final concentration was 0.3% in the human c-mpl-Ba / F3 cell proliferation test system described in (1) It added so that it might become plasma, cell growth activity was measured, and the cell growth activity (%) of each plasma when the maximum cell growth activity of each test compound was made into 100% was calculated | required. The results are shown in Table 2.
From the above results, it was confirmed that the compound of the present invention has oral activity in mice.
The medicament of the present invention can be prepared by a commonly used method using the compound of the present invention and a simple substance for pharmaceutical use, excipients, and other additives usually used for formulation. Administration is any of oral administration by tablets, pills, capsules, granules, powders, liquids, injections such as intravenous injection, intramuscular injection, or parenteral administration by 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 a solid composition, the compound of the present invention comprises at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. Mixed. According to a conventional method, the composition is made of an additive other than an inert diluent, such as a lubricant such as magnesium stearate, a disintegrant such as calcium calcium glycolate, a stabilizer such as lactose, glutamic acid or aspartic acid. It may contain a solubilizing agent. 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,
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 in 2 to 4 divided doses. When administered intravenously, 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 divided into once to several times a day. Administer. The dosage is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
以下、実施例により本発明を具体的に説明する。なお、実施例において使用される原料化合物には新規な物質も含まれており、そのような原料化合物の公知物からの製造法を参考例として説明する。
参考例1
4−クロロ−2−アセチルチオフェン4.18g、ジエチルエーテル30mlの溶液に氷冷下にて臭素1.5mlを加え、室温にて2時間攪拌した。反応液に水を加え分液し、得られる有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去しブロム体を得た。ブロム体のEtOH30mlの溶液に室温でチオ尿素2.1gを加え、80℃にて一晩攪拌した。析出する固体をろ過し得られる溶液を減圧留去しクロロホルムを加えた後、炭酸カリウム水溶液、飽和食塩水で有機層を洗浄後、硫酸ナトリウムで乾燥した。溶媒を減圧留去後、得られた残渣をヘキサン:酢酸エチル=1:1の溶液で洗浄し、2.57gの2−アミノ−4−(4−クロロチオフェン−2−イル)チアゾールを得た。
質量分析データ(FAB−MS(M+H)+):217.
参考例2
参考例1の化合物0.5g、N,N−ジメチルホルムアミド5mlの溶液に氷冷下にてN−ブロモコハク酸イミド0.45gを加え、同温にて50分間攪拌した。反応液にシクロヘキシルピペラジン0.6g、トリエチルアミン0.6mlを順に加え、70℃にて3日間攪拌した。反応液を減圧留去しクロロホルムを加えた後、炭酸カリウム水溶液、飽和食塩水で有機層を洗浄後、硫酸ナトリウムで乾燥した。溶媒を減圧留去後、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1)にて精製し、300mgの2−アミノ−4−(4−クロロチオフェン−2−イル)−5−(4−シクロヘキシルピペラジン−1−イル)チアゾールを得た。
質量分析データ(FAB−MS(M+H)+):383.
参考例3
参考例2の化合物1.0g、ピリジン30mlの溶液に、5,6−ジクロロニコチン酸602mgを加え、−25℃においてオキシ塩化リン0.27mlを加え、室温に昇温後4時間攪拌した。反応液を減圧留去し、水、炭酸カリウムを加えた後、クロロホルムにて抽出、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去後、得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=200:1〜100:1)にて精製し、1.21gの5,6−ジクロロ−N−[4−(4−クロロチオフェン−2−イル)−5−(4−シクロヘキシルピペラジン−1−イル)チアゾール−2−イル]ニコチンアミドを得た。
質量分析データ(FAB−MS(M+H)+):556.
参考例4
参考例3の化合物750mg、テトラヒドロフラン10mlの溶液に、室温下イソニペコチン酸エチル2.1mlを加え、50℃に昇温後5時間攪拌した。反応液にクロロホルムを加えた後、飽和炭酸水素ナトリウム水溶液、飽和食塩水で有機層を洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去後、得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=200:1〜100:1)にて精製し、881mgの1−(3−クロロ−5−{[4−(4−クロロチオフェン−2−イル)−5−(4−シクロヘキシルピペラジン−1−イル)チアゾール−2−イル]カルバモイル}ピリジン−2−イル)ピペリジン−4−カルボン酸エチルエステルを得た。
質量分析データ(FAB−MS(M+H)+):677.
実施例1 化合物Aの製造
参考例4の化合物1.00g、EtOH10mlの溶液に、室温下1M水酸化ナトリウム水溶液4.45mlを加え、17時間攪拌した。不溶物をろ去後、得られた溶液にマレイン酸345mgの7.5ml水溶液を加え1時間攪拌し、析出物をろ取した。このものに80%EtOH水32ml、マレイン酸519mgを加え16時間攪拌、固体をろ取した。さらにマレイン酸60mgを加え、80%EtOH水15mlより再結晶し、638mgの1−(3−クロロ−5−{[4−(4−クロロチオフェン−2−イル)−5−(4−シクロヘキシルピペラジン−1−イル)チアゾール−2−イル]カルバモイル}ピリジン−2−イル)ピペリジン−4−カルボン酸マレイン酸塩を得た。
1H−NMR(テトラメチルシランを内部標準とし、DMSO−d6を測定溶媒とした。)δ:1.08−1.21(1H,m)1.22−1.46(4H,m)1.60−1.74(3H,m),1.82−1.98(4H,m),2.05−2.15(2H,m),2.50−2.58(1H,m),3.04(2H,t,J=11.2Hz),3.08−3.60(9H,m),3.99(2H,d,J=13.2Hz),6.05(2H,s),7.50(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.41(1H,d,J=1.9Hz),8.84(1H,d,J=1.9Hz),12.68(1H,brs).
質量分析データ(FAB−MS(M+H)+):649.
実施例1の化合物の熱重量分析データを図1に示す。Hereinafter, the present invention will be described specifically by way of examples. In addition, the raw material compound used in an Example includes 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
To a solution of 4.18 g of 4-chloro-2-acetylthiophene and 30 ml of diethyl ether was added 1.5 ml of bromine under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution for liquid separation, and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a bromide. 2.1 g of thiourea was added at room temperature to a solution of 30 ml of EtOH in bromo form and stirred overnight at 80 ° C. The solution obtained by filtering the precipitated solid was distilled off under reduced pressure and chloroform was added. The organic layer was washed with an aqueous potassium carbonate solution and saturated brine, and then dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was washed with a solution of hexane: ethyl acetate = 1: 1 to obtain 2.57 g of 2-amino-4- (4-chlorothiophen-2-yl) thiazole. .
Mass spectrometry data (FAB-MS (M + H) + ): 217.
Reference example 2
To a solution of 0.5 g of the compound of Reference Example 1 and 5 ml of N, N-dimethylformamide was added 0.45 g of N-bromosuccinimide under ice cooling, and the mixture was stirred at the same temperature for 50 minutes. To the reaction solution, 0.6 g of cyclohexylpiperazine and 0.6 ml of triethylamine were sequentially added, followed by stirring at 70 ° C. for 3 days. The reaction solution was distilled off under reduced pressure and chloroform was added. The organic layer was washed with an aqueous potassium carbonate solution and saturated brine, and then dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and 300 mg of 2-amino-4- (4-chlorothiophen-2-yl)- 5- (4-Cyclohexylpiperazin-1-yl) thiazole was obtained.
Mass spectrometry data (FAB-MS (M + H) + ): 383.
Reference example 3
To a solution of 1.0 g of the compound of Reference Example 2 and 30 ml of pyridine, 602 mg of 5,6-dichloronicotinic acid was added, 0.27 ml of phosphorus oxychloride was added at −25 ° C., and the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was evaporated under reduced pressure, water and potassium carbonate were added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 200: 1 to 100: 1), and 1.21 g of 5,6-dichloro-N- [4- ( 4-Chlorothiophen-2-yl) -5- (4-cyclohexylpiperazin-1-yl) thiazol-2-yl] nicotinamide was obtained.
Mass spectrometry data (FAB-MS (M + H) + ): 556.
Reference example 4
To a solution of 750 mg of the compound of Reference Example 3 and 10 ml of tetrahydrofuran was added 2.1 ml of ethyl isonipecotate at room temperature, and the mixture was heated to 50 ° C. and stirred for 5 hours. Chloroform was added to the reaction solution, and then the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 200: 1 to 100: 1), and 881 mg of 1- (3-chloro-5-{[4- ( 4-Chlorothiophen-2-yl) -5- (4-cyclohexylpiperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid ethyl ester was obtained.
Mass spectrometry data (FAB-MS (M + H) + ): 677.
Example 1 Production of Compound A To a solution of 1.00 g of the compound of Reference Example 4 and 10 ml of EtOH, 4.45 ml of 1M aqueous sodium hydroxide solution was added at room temperature and stirred for 17 hours. After removing insolubles by filtration, 7.5 ml aqueous solution of 345 mg maleic acid was added to the resulting solution and stirred for 1 hour, and the precipitate was collected by filtration. To this, 32 ml of 80% aqueous EtOH and 519 mg of maleic acid were added and stirred for 16 hours, and the solid was collected by filtration. Further, 60 mg of maleic acid was added and recrystallized from 15 ml of 80% aqueous EtOH to give 638 mg of 1- (3-chloro-5-{[4- (4-chlorothiophen-2-yl) -5- (4-cyclohexylpiperazine). -1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleate was obtained.
1 H-NMR (tetramethylsilane was used as an internal standard and DMSO-d 6 was used as a measurement solvent) δ: 1.08-1.21 (1H, m) 1.22-1.46 (4H, m) 1.60-1.74 (3H, m), 1.82-1.98 (4H, m), 2.05-2.15 (2H, m), 2.50-2.58 (1H, m ), 3.04 (2H, t, J = 11.2 Hz), 3.08-3.60 (9H, m), 3.99 (2H, d, J = 13.2 Hz), 6.05 (2H) , S), 7.50 (1H, d, J = 1.5 Hz), 7.57 (1H, d, J = 1.5 Hz), 8.41 (1H, d, J = 1.9 Hz), 8 .84 (1H, d, J = 1.9 Hz), 12.68 (1H, brs).
Mass spectrometry data (FAB-MS (M + H) + ): 649.
The thermogravimetric analysis data of the compound of Example 1 is shown in FIG.
図1:実施例1の化合物の熱重量分析データを示す図である。1 is a graph showing thermogravimetric analysis data of the compound of Example 1. FIG.
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DK1466912T3 (en) | 2002-01-18 | 2013-07-01 | Astellas Pharma Inc | 2-ACYLAMINOTHIAZOLD DERIVATIVES OR SALTS THEREOF |
JP4665769B2 (en) * | 2005-01-12 | 2011-04-06 | アステラス製薬株式会社 | Method for producing acylaminothiazole derivative |
WO2007054783A2 (en) * | 2005-11-08 | 2007-05-18 | Astellas Pharma Inc. | Compositions and methods for treating thrombocytopenia |
WO2008021283A2 (en) * | 2006-08-08 | 2008-02-21 | Akarx, Inc. | Compositions and methods for increasing blood platelet levels in humans |
US20090304634A1 (en) * | 2006-12-12 | 2009-12-10 | Smithkline Beecham Corporation | Novel Combinations |
TWI384986B (en) * | 2007-01-17 | 2013-02-11 | Lg Life Sciences Ltd | Maleic acid monosalt of antiviral agent and pharmaceutical composition containing the same |
UY30915A1 (en) * | 2007-02-16 | 2008-09-02 | Smithkline Beecham Corp | CANCER TREATMENT METHOD |
EP2184279B1 (en) | 2007-07-31 | 2014-11-12 | Shionogi&Co., Ltd. | Pharmaceutical composition containing optically active compound having thrombopoietin receptor agonist activity and intermediate thereof |
US8476249B2 (en) | 2009-05-07 | 2013-07-02 | Glaxosmithkline Llc | Method of treating thrombocytopenia |
SI3127427T1 (en) | 2009-05-29 | 2020-07-31 | Novartis Ag | Methods of administration of thrombopoietin agonist compounds |
JP2014144916A (en) | 2011-08-03 | 2014-08-14 | Astellas Pharma Inc | Crystal of 2-acylamino thiazole compound |
CN106749226B (en) * | 2017-03-15 | 2019-12-20 | 广东赛拓医药科技有限公司 | Preparation method of avatrombopag maleate crystal form C |
CN107383000A (en) * | 2017-08-07 | 2017-11-24 | 瑞阳制药有限公司 | The preparation method of thrombocythemia agent |
WO2020044364A1 (en) | 2018-08-27 | 2020-03-05 | Mylan Laboratories Limited | Polymorphic forms of avatrombopag maleate |
CN112480106B (en) * | 2020-11-17 | 2022-09-02 | 南京海纳医药科技股份有限公司 | Preparation method of Alvatripopa maleate impurity |
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CN115504975A (en) * | 2022-10-18 | 2022-12-23 | 河北常山凯库得生物技术有限公司 | Preparation method of Alvatripopa maleate intermediate |
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CN112409350B (en) * | 2020-11-27 | 2023-12-19 | 上海迪赛诺生物医药有限公司 | Preparation method of maleic acid atorvastatin crystal form C |
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