JP2022029880A - Crystall form of 3-[8-[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxyoctyl]oxetane-3-carboxylic acid and method for producing the same - Google Patents
Crystall form of 3-[8-[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxyoctyl]oxetane-3-carboxylic acid and method for producing the same Download PDFInfo
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Abstract
Description
本発明は、３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸の結晶形及びその製造方法に関する。さらに詳しくは、２０－ヒドロキシエイコサテトラエン酸（２０－Ｈｙｄｒｏｘｙｅｉｃｏｓａｔｅｔｒａｅｎｏｉｃ ａｃｉｄ、以下、「２０－ＨＥＴＥ」と記載することもある。）を産生する酵素の阻害物質である３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸の結晶形及びその製造方法に関する。 The present invention relates to a crystal form of 3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid and a method for producing the same. More specifically, it is an inhibitor of an enzyme that produces 20-hydroxyeicosatetraenoic acid (20-Hydroxyeicosate traenoic acid, hereinafter also referred to as "20-HETE"), which is an inhibitor of 3- [8- [6-]. (1,2,4-Triazol-1-yl) Pyridine-3-yl] Oxyoctyl] The crystal form of oxetane-3-carboxylic acid and a method for producing the same.
アラキドン酸から産生される生理活性物質として、シクロオキシゲナーゼによって産生されるプロスタグランジン類及びリポキシゲナーゼによって産生されるロイコトリエン類に加えて、近年ではチトクロームＰ４５０に属する酵素によってアラキドン酸から産生される２０－ＨＥＴＥが生体内で多彩な働きをしていることが明らかになりつつある。これまでに２０－ＨＥＴＥは、脳血管や腎臓等の主要臓器において血管緊張性を調節することや細胞増殖を惹起することが明らかにされており、生体内で重要な生理作用を演じていると共に各種脳血管疾患、腎疾患、循環器疾患等の病態に深く関与していることが示唆されている（非特許文献１～３）。さらに、近年では多発性嚢胞腎の病態形成に２０－ＨＥＴＥが関与していることが明らかになってきている。多発性嚢胞腎は、常染色体優性多発性嚢胞腎及び常染色体劣性多発性嚢胞腎に分類され、腎臓に多数の嚢胞を形成して腎機能に障害をもたらす遺伝性嚢胞性腎疾患である。多発性嚢胞腎を発症する病態動物に対して、２０－ＨＥＴＥ阻害薬は細胞内増殖シグナルを抑制するとともに腎嚢胞改善効果を発揮することが示唆されている（非特許文献４）。また、常染色体優性多発性嚢胞腎患者においては、腎容積増大及び腎機能低下と血漿中２０－ＨＥＴＥ濃度上昇に相関関係が認められており、多発性嚢胞腎の病態進行に２０－ＨＥＴＥが関連していることが示唆されている（非特許文献５）。 Physiologically active substances produced from arachidonic acid include prostaglandins produced by cyclooxygenase and leukotrienes produced by lipoxygenase, as well as 20-HETE produced from arachidonic acid by an enzyme belonging to cytochrome P450 in recent years. It is becoming clear that it has various functions in the living body. It has been clarified that 20-HETE regulates vascular tone and induces cell proliferation in major organs such as cerebrovascular and kidney, and plays an important physiological action in vivo. It has been suggested that it is deeply involved in pathological conditions such as various cerebrovascular diseases, renal diseases, and cardiovascular diseases (Non-Patent Documents 1 to 3). Furthermore, in recent years, it has become clear that 20-HETE is involved in the pathogenesis of polycystic kidney disease. Polycystic kidney disease is a hereditary cystic kidney disease classified into autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease, which forms a large number of cysts in the kidney and causes impaired renal function. It has been suggested that 20-HETE inhibitors suppress intracellular proliferation signals and exert an effect of improving renal cysts in pathological animals that develop polycystic kidney disease (Non-Patent Document 4). In addition, in patients with autosomal dominant polycystic kidney disease, a correlation was observed between increased renal volume and decreased renal function and increased plasma 20-HETE concentration, and 20-HETE was associated with the progression of polycystic kidney disease. It is suggested that this is done (Non-Patent Document 5).
２０－ＨＥＴＥを産生する酵素の阻害物質としては、ヒドロキシホルムアミジン誘導体（特許文献１）やフェニルアゾール骨格を有する化合物であるヘテロ環誘導体（特許文献２）やフェニルアゾール化合物（特許文献３）等が報告されている。特許文献２では、ピラゾリル等のヘテロアリールで置換されたピリジン化合物の開示もあるが、ピリジンの３位置換に限定されている。また、特許文献４では、ピリジンの２位にトリアゾリル等のヘテロアリールで置換されたピリジン化合物の開示があるが、ピリジンの５位に置換する基は特定されており、カルボキシ等酸性を示す基の開示は無い。 Examples of the inhibitor of the enzyme that produces 20-HETE include a hydroxyform amidine derivative (Patent Document 1), a heterocyclic derivative (Patent Document 2) which is a compound having a phenylazole skeleton, and a phenylazole compound (Patent Document 3). It has been reported. Patent Document 2 also discloses a pyridine compound substituted with a heteroaryl such as pyrazolyl, but is limited to a 3-position substitution of pyridine. Further, Patent Document 4 discloses a pyridine compound in which the 2-position of pyridine is substituted with a heteroaryl such as triazolyl, but the group substituted at the 5-position of pyridine is specified, and the group exhibiting acidity such as carboxy is specified. There is no disclosure.
また、医薬品の観点からは、工業的規模における取扱いし易く、保存安定性に優れた物
理的特性を有する化合物が望まれている。
From the viewpoint of pharmaceutical products, compounds having physical properties that are easy to handle on an industrial scale and have excellent storage stability are desired.
本発明の目的は、優れた２０－ＨＥＴＥを産生する酵素を阻害する作用を有し、一定の品質を有する単一の結晶として再現性良く得られ、医薬品及び医薬品原料の製造に用いられる原薬の結晶として安定的に供給されることが可能で、保存安定性に優れた物理学的特性を有する新規な化合物の結晶形及びその製造方法を提供することにある。 An object of the present invention is to have an action of inhibiting an enzyme that produces excellent 20-HETE, to obtain it as a single crystal having a certain quality with good reproducibility, and to use it as a drug substance used in the production of pharmaceutical products and raw materials for pharmaceutical products. It is an object of the present invention to provide a crystal form of a novel compound which can be stably supplied as a crystal of the above and has excellent storage stability and physical properties, and a method for producing the same.
本発明者らは、上記課題を達成すべく鋭意検討を重ねた結果、下記式［Ｉ］で表される３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸（以下、化合物［Ｉ］又は本発明化合物と記すこともある）が、優れた２０－ＨＥＴＥを産生する酵素を阻害する作用を有すること、また、上記物理的特性に優れた化合物［Ｉ］の結晶及びその製造方法を提供することができることを発見し、本発明を完成するに至った。 As a result of diligent studies to achieve the above problems, the present inventors have made 3- [8- [6- (1,2,4-triazol-1-yl) pyridine represented by the following formula [I]. -3-yl] Oxyoctyl] Oxetane-3-carboxylic acid (hereinafter, also referred to as compound [I] or the compound of the present invention) has an action of inhibiting an enzyme that produces excellent 20-HETE. Further, they have discovered that it is possible to provide a crystal of the compound [I] having excellent physical properties and a method for producing the same, and have completed the present invention.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
（１）本発明のひとつの態様は、
下記（ａ）～（ｂ）の物性を有する、３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸の結晶（以下、Ａ形結晶と記すこともある）を提供することである。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝４．７度、１４．１度、１７．５度、及び１８．９度にピークを有する；
並びに
（ｂ）示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）において、吸熱ピークが１２１℃～１２５℃にある。
(1) One aspect of the present invention is
Of 3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid having the following physical properties of (a) to (b) It is to provide a crystal (hereinafter, also referred to as an A-type crystal).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.7 degrees, 14.1 degrees, 17.5 degrees, and 18.9 degrees;
In addition, in (b) differential thermal analysis / thermal mass measurement (TG / DTA), the endothermic peak is at 121 ° C to 125 ° C.
（２）本発明の他の態様は、
３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸に下記溶媒群Ａから選ばれる１種の溶媒を加えて、溶液とした後、結晶化させ、得られた結晶を乾燥させることを特徴とする下記（ａ）～（ｂ）の物性を有する結晶の製造方法であって、
溶媒群Ａは、
酢酸エチル及びｎ－ヘキサンの混合液、酢酸エチル、ＭＴＢＥ、トルエン、ＴＨＦ、メタノール、エタノール、２－プロパノール、アセトン、アセトニトリル、並びにＤＭＦ
からなる群である、前記の製造方法を提供することである。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝４．７度、１４．１度、１７．５度、及び１８．９度にピークを有する；
並びに
（ｂ）示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）において、吸熱ピークが１２１℃～１２５℃にある。
(2) Another aspect of the present invention is
3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid is added with one solvent selected from the following solvent group A. A method for producing crystals having the following physical properties (a) to (b), which comprises preparing a solution, crystallization, and drying the obtained crystals.
Solvent group A
A mixture of ethyl acetate and n-hexane, ethyl acetate, MTBE, toluene, THF, methanol, ethanol, 2-propanol, acetone, acetonitrile, and DMF.
It is to provide the said manufacturing method which is a group consisting of.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.7 degrees, 14.1 degrees, 17.5 degrees, and 18.9 degrees;
In addition, in (b) differential thermal analysis / thermal mass measurement (TG / DTA), the endothermic peak is at 121 ° C to 125 ° C.
（３）本発明の他の態様としては、
（１）に記載の、３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸又はその塩の結晶を有効成分として含有する医薬を提供することである。
(3) As another aspect of the present invention,
The crystals of 3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid or a salt thereof described in (1) are effective. It is to provide a medicine contained as an ingredient.
（４）本発明の他の態様としては、
２０－ＨＥＴＥ産生酵素阻害剤である（３）に記載の医薬を提供することである。
(4) As another aspect of the present invention,
To provide the pharmaceutical agent according to (3), which is a 20-HETE-producing enzyme inhibitor.
（５）本発明の他の態様としては、
多発性嚢胞腎の予防又は改善剤である（３）に記載の医薬を提供することである。
(5) As another aspect of the present invention,
It is to provide the medicine according to (3) which is a preventive or ameliorating agent for polycystic kidney disease.
本発明により、２０－ＨＥＴＥ産生する酵素を阻害する作用を有する３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸の結晶を提供することが可能となった。該結晶は、室温付近の温度で安定な結晶形であり、保存安定性に優れている。また、本発明により、上記結晶を、同一品質で安定して得るための新規な製造方法を提供することができた。
According to the present invention, 3- [8- [6- (1,2,4-triazol-1-yl) pyridine-3-yl] oxyoctyl] oxetane-3- [8- [6- (1,2,4-triazol-1-yl) pyridine-3-yl] having an action of inhibiting an enzyme producing 20-HETE. It has become possible to provide crystals of carboxylic acid. The crystal has a stable crystal form at a temperature near room temperature and is excellent in storage stability. Further, according to the present invention, it was possible to provide a novel manufacturing method for stably obtaining the above crystals with the same quality.
以下、本発明を実施するための態様を具体的に説明する。 Hereinafter, embodiments for carrying out the present invention will be specifically described.
本発明化合物である３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸は、前記に示した化学構造式を有している。 The compound of the present invention, 3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid, has the chemical structural formula shown above. have.
本発明化合物の結晶（以下、「本発明結晶」ということがある）は、上述のように一定の品質を有する単一の結晶として再現性良く得られ、医薬品の製造に用いられる原薬の結晶として安定的に供給されることが可能で、保存安定性に優れたものである。 The crystal of the compound of the present invention (hereinafter, may be referred to as "crystal of the present invention") is obtained with good reproducibility as a single crystal having a certain quality as described above, and is a crystal of a drug substance used for manufacturing a pharmaceutical product. It can be stably supplied as a product and has excellent storage stability.
本発明化合物の結晶は、たとえば、以下の方法により製造することができる。 The crystal of the compound of the present invention can be produced, for example, by the following method.
所定の有機溶媒に化合物［Ｉ］を加熱溶解させた後、徐冷することにより結晶を析出させ、析出した結晶をろ過、遠心分離等により溶媒と分離した後に乾燥させることにより化合物［Ｉ］の結晶を得ることができる。なお、再結晶は、１度のみならず２度以上繰り返してもよいが、通常は１度のみ再結晶を行う。 After the compound [I] is heated and dissolved in a predetermined organic solvent, crystals are precipitated by slow cooling, and the precipitated crystals are separated from the solvent by filtration, centrifugation or the like and then dried to obtain the compound [I]. Crystals can be obtained. The recrystallization may be repeated not only once but also twice or more, but usually, recrystallization is performed only once.
冷却させる時間は、１０秒以上であれば特に制限されないが、通常１０分から２４時間であり、好ましくは３０分から８時間、より好ましくは３０分から５時間である。 The cooling time is not particularly limited as long as it is 10 seconds or more, but is usually 10 minutes to 24 hours, preferably 30 minutes to 8 hours, and more preferably 30 minutes to 5 hours.
また、結晶化に際しては種晶を使用することができる。種晶は、晶析のための溶液が入った容器の壁をスパチュラ（Ｓｐａｔｕｌａ）でこするなど、当業者にとって良く知られた方法で取得しておくことができる。
In addition, seed crystals can be used for crystallization. Seed crystals can be obtained by a method well known to those skilled in the art, such as rubbing the wall of a container containing a solution for crystallization with a spatula.
本発明化合物のＡ形結晶について、以下に説明する。 The A-type crystal of the compound of the present invention will be described below.
化合物［Ｉ］のＡ形結晶は、以下の（ａ）～（ｂ）の物性を有する。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝４．７度、１４．１度、１７．５度、及び１８．９度にピークを有する；並びに
（ｂ）示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）において、吸熱ピークが１２１℃～１２５℃にある。
The A-type crystal of compound [I] has the following physical characteristics (a) to (b).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.7 degrees, 14.1 degrees, 17.5 degrees, and 18.9 degrees; and (b) differential thermal analysis / heat. In mass measurement (TG / DTA), the endothermic peak is at 121 ° C to 125 ° C.
化合物［Ｉ］のＡ形結晶の粉末Ｘ線回折パターンは図１に、示差熱分析／熱質量測定カーブは図２に示した通りである。 The powder X-ray diffraction pattern of the A-type crystal of compound [I] is as shown in FIG. 1, and the differential thermal analysis / thermal mass measurement curve is as shown in FIG.
なお、粉末Ｘ線結晶回折による特徴的なピークは、測定条件によって変動することがある。そのため、本発明化合物の粉末Ｘ線結晶回折のピークについて、誤差が生じたり、明確でなかったりする場合がある。 The characteristic peak due to powder X-ray crystal diffraction may fluctuate depending on the measurement conditions. Therefore, the peak of the powder X-ray crystal diffraction of the compound of the present invention may have an error or may not be clear.
図１～２から分かるように、本発明の製造方法により製造される化合物［Ｉ］のＡ形結晶は、基本的に純度の高い結晶であることが分かる。結晶の純度は高いものが望ましく、好ましくは他の結晶形のものを実質的に含まないものである。
また、後述の実施例に示されるように、本発明の製造方法により製造される化合物［Ｉ］のＡ形結晶は、一定の品質を有する単一の結晶として再現性良く得られ、医薬品及び医薬品原料の製造に用いられる原薬の結晶として安定的に供給されることが可能で、保存安定性に優れた物理学的特性を有する。
As can be seen from FIGS. 1 and 2, it can be seen that the A-type crystal of the compound [I] produced by the production method of the present invention is basically a crystal having high purity. It is desirable that the crystal has a high purity, and preferably it does not substantially contain other crystal forms.
Further, as shown in Examples described later, the A-type crystal of the compound [I] produced by the production method of the present invention can be obtained with good reproducibility as a single crystal having a certain quality, and is a pharmaceutical product and a pharmaceutical product. It can be stably supplied as crystals of the drug substance used in the production of raw materials, and has excellent physical properties with excellent storage stability.
次に、化合物［Ｉ］のＡ形結晶の製造方法について説明する。
化合物［Ｉ］のＡ形結晶は、たとえば、以下の方法により製造することができる。
Next, a method for producing an A-type crystal of compound [I] will be described.
The A-type crystal of compound [I] can be produced, for example, by the following method.
所定の溶媒に化合物［Ｉ］を加熱溶解させた後、徐冷することにより結晶を析出させ、析出した結晶をろ取、遠心分離等により溶媒と分離した後に乾燥させることにより化合物［Ｉ］のＡ形結晶を得ることができる。 After the compound [I] is heated and dissolved in a predetermined solvent, crystals are precipitated by slow cooling, and the precipitated crystals are separated from the solvent by filtration, centrifugation or the like and then dried to obtain the compound [I]. A-type crystals can be obtained.
溶媒に溶解前の、原料の化合物［Ｉ］は、非晶質又は結晶である。 The raw material compound [I] before being dissolved in the solvent is amorphous or crystalline.
前記所定の溶媒の具体例としては、酢酸エチル、ジエチルエーテル、ＭＴＢ（ｔｅｒｔ－ブチルメチルエーテル）、トルエン、ＴＨＦ（テトラヒドロフラン）、メタノール、エタノール、２－プロパノール、アセトン、アセトニトリル、又はＤＭＦ（Ｎ，Ｎ－ジメチルホルムアミド）が挙げられる。
また、上記の溶媒に、水、ｎ－ヘプタン、ｎ－ヘキサン等を加え、混合液とすることもできる。混合液の具体例として、ｎ－ヘプタン及びｎ－ヘキサンからなる群から選ばれる１種以上の溶媒と酢酸エチルとの混合溶媒が挙げられる。
好ましい溶媒としては、ｎ－ヘキサンと酢酸エチルとの混合溶媒、酢酸エチル、メタノール、エタノール、２－プロパノールが挙げられる。
Specific examples of the predetermined solvent include ethyl acetate, diethyl ether, MTB (tert-butyl methyl ether), toluene, THF (tetrahydrofuran), methanol, ethanol, 2-propanol, acetone, acetonitrile, or DMF (N, N). -Dimethylformamide).
Further, water, n-heptane, n-hexane and the like can be added to the above solvent to prepare a mixed solution. Specific examples of the mixed solution include a mixed solvent of ethyl acetate and one or more solvents selected from the group consisting of n-heptane and n-hexane.
Preferred solvents include a mixed solvent of n-hexane and ethyl acetate, ethyl acetate, methanol, ethanol and 2-propanol.
なお、ｎ－ヘプタン及びｎ－ヘキサンからなる群から選ばれる１種以上の溶媒と酢酸エチルとの混合溶媒における混合比は、適宜に変更することができる。 The mixing ratio of one or more solvents selected from the group consisting of n-heptane and n-hexane and the mixed solvent of ethyl acetate can be appropriately changed.
化合物［Ｉ］のＡ形結晶の結晶化は、通常０℃～還流温度で行う。好ましくは、０℃～１００℃であり、より好ましくは、２０℃～６０℃であり、さらに好ましくは、２０℃～３０℃である。 Crystallization of the A-type crystal of compound [I] is usually carried out at 0 ° C. to a reflux temperature. It is preferably 0 ° C to 100 ° C, more preferably 20 ° C to 60 ° C, and even more preferably 20 ° C to 30 ° C.
析出した化合物［Ｉ］のＡ形結晶は、溶液からろ取、遠心分離などにより溶媒と分離することができる。 The A-type crystals of the precipitated compound [I] can be separated from the solvent by filtration from the solution, centrifugation or the like.
化合物［Ｉ］のＡ形結晶の乾燥は、通常１００℃以下で行う。好ましくは、２０℃～６０℃であり、より好ましくは、２０℃～３０℃である。
Drying of the A-type crystal of compound [I] is usually carried out at 100 ° C. or lower. It is preferably 20 ° C to 60 ° C, and more preferably 20 ° C to 30 ° C.
本発明の化合物は、互変異性を有し、種々の互変異性体が存在する。本発明の化合物は、それらの異性体、及びそれらの異性体を任意の割合で含んだ混合物も含む。 The compound of the present invention has tautomerism, and various tautomers exist. The compounds of the present invention also include isomers thereof and mixtures containing the isomers in any proportion.
本明細書において、製薬学的に許容される塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩、硫酸塩、硝酸塩のような鉱酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、トリフルオロメタンスルホン酸塩のようなスルホン酸塩、シュウ酸塩、酒石酸塩、クエン酸塩、マレイン酸塩、コハク酸塩、酢酸塩、トリフルオロ酢酸塩、安息香酸塩、マンデル酸塩、アスコルビン酸塩、乳酸塩、グルコン酸塩、リンゴ酸塩のような有機酸塩等の酸付加塩、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩、又は、リチウム塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩のような無機塩若しくはアンモニウム塩、トリエチルアミン塩、ジイソプロピルアミン塩、シクロヘキシルアミン塩のような有機塩基との塩が挙げられる。なお、塩には、含水塩が含まれる。
さらに、本発明の化合物又はその塩が水和物又は溶媒和物を形成する場合、それらも本発明の化合物又はその塩の範囲内に含まれる。
In the present specification, pharmaceutically acceptable salts include, for example, hydrochlorides, hydrobromates, hydroiodides, phosphates, sulfates, mineral salts such as nitrates, and methanesulfone. Sulfates such as acid salts, ethane sulfonates, benzene sulfonates, p-toluene sulfonates, trifluoromethane sulfonates, oxalates, tartrates, citrates, maleates, succinates. , Acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, acid addition salts such as organic acid salts such as malate, glycine, lysine, arginine Amino acid salts such as salts, ornithine salts, glutamates, asparagitates, or inorganic or ammonium salts such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, triethylamine salts, diisopropylamine salts, cyclohexyl Examples include salts with organic bases such as amine salts. The salt includes hydrous salt.
Further, when the compound of the present invention or a salt thereof forms a hydrate or a solvate, they are also included in the range of the compound of the present invention or a salt thereof.
２０－ＨＥＴＥ産生酵素とは、アラキドン酸のω位水酸化を触媒し、アラキドン酸を基質として２０－ＨＥＴＥを産生するチトクロームＰ４５０ ４Ａ１１、４Ｆ２のことである。
さて、前述のように、２０－ＨＥＴＥは生体内で多彩な働きをしており、多発性嚢胞腎の病態形成や、各種脳血管疾患、腎疾患、循環器疾患等の病態に関与している。
したがって、２０－ＨＥＴＥを産生する酵素を阻害することによって、多発性嚢胞腎、多発性嚢胞腎に関連する疾患、多発性嚢胞腎に関連する症状を予防又は改善することができる。また、高血圧、脳血管疾患、虚血性心疾患、慢性腎不全、動脈硬化、脂肪肝、癌を予防又は改善することができる。
The 20-HETE-producing enzyme is a cytochrome P450 4A11, 4F2 that catalyzes the ω-position hydroxylation of arachidonic acid and produces 20-HETE using arachidonic acid as a substrate.
As mentioned above, 20-HETE has various functions in the living body and is involved in the pathogenesis of polycystic kidney disease and various pathological conditions such as cerebrovascular disease, renal disease, and cardiovascular disease. ..
Therefore, by inhibiting the enzyme that produces 20-HETE, polycystic kidney disease, diseases associated with polycystic kidney disease, and symptoms associated with polycystic kidney disease can be prevented or ameliorated. In addition, hypertension, cerebrovascular disease, ischemic heart disease, chronic renal failure, arteriosclerosis, fatty liver, and cancer can be prevented or ameliorated.
本発明の化合物は、２０－ＨＥＴＥを産生する酵素を阻害する作用を有する。よって、本発明の化合物は、２０－ＨＥＴＥ産生酵素阻害剤、又は多発性嚢胞腎の予防又は改善剤の有効成分として用いることができる。
また、本発明の化合物は、高血圧、脳血管疾患、虚血性心疾患、慢性腎不全、動脈硬化、脂肪肝、癌の予防又は改善剤の有効成分として用いることもできる。
The compound of the present invention has an action of inhibiting an enzyme that produces 20-HETE. Therefore, the compound of the present invention can be used as an active ingredient of a 20-HETE-producing enzyme inhibitor or a preventive or ameliorating agent for polycystic kidney disease.
The compound of the present invention can also be used as an active ingredient of a prophylactic or ameliorating agent for hypertension, cerebrovascular disease, ischemic heart disease, chronic renal failure, arteriosclerosis, fatty liver and cancer.
ここで、「多発性嚢胞腎」には、遺伝子変異により両側腎臓に多数の嚢胞が進行性に発生及び増大する「常染色体優性多発性嚢胞腎」と「常染色体劣性多発性嚢胞腎」が含まれる。「多発性嚢胞腎に関連する疾患」には、慢性腎不全、高血圧、血管障害、肝臓及び膵臓の嚢胞、尿路感染症、肝胆道系感染症、尿路結石などが挙げられる。また、「多発性嚢胞腎に関連する症状」としては、疼痛、血尿、腹部膨満が含まれる。 Here, "polycystic kidney disease" includes "autosomal dominant multiple cystic kidney disease" and "autosomal recessive polycystic kidney disease" in which a large number of cysts are progressively developed and increased in both kidneys due to gene mutation. Is done. "Disease associated with polycystic kidney disease" includes chronic renal failure, hypertension, vascular disorders, liver and pancreatic cysts, urinary tract infections, hepatobiliary system infections, urinary stones and the like. In addition, "symptoms related to polycystic kidney disease" include pain, hematuria, and abdominal distension.
なお、本発明の化合物の２０－ＨＥＴＥを産生する酵素を阻害する作用を評価するには、例えば、後述の本明細書の試験例に記載した方法など、公知の手法に従って行うことができる。 In addition, in order to evaluate the action of the compound of the present invention to inhibit the enzyme that produces 20-HETE, it can be carried out according to a known method such as, for example, the method described in the test examples of the present specification described later.
本発明に係る医薬について、含有する本発明の化合物である２０－ＨＥＴＥを産生する酵素を阻害する化合物又はその製薬学的に許容される塩は、単独に、又は薬学的或いは薬剤学的に許容される添加剤と共に投与することができる。 With respect to the drug according to the present invention, the compound that inhibits the enzyme that produces 20-HETE, which is the compound of the present invention, or a pharmaceutically acceptable salt thereof may be used alone, or pharmaceutically or pharmaceutically acceptable. Can be administered with the additives to be added.
添加剤としては、常用の賦形剤又は希釈剤、そして、必要に応じて一般に使用される結合剤、崩壊剤、潤滑剤、被覆剤、糖衣剤、pH調整剤、溶解剤又は水性若しくは非水性溶媒を使用することができる。具体的には、水、乳糖、デキストロース、フラクトース、ショ糖、ソルビトール、マンニトール、ポリエチレングリコール、プロピレングリコール、デンプン、コーンスターチ、ガム、ゼラチン、アルギネート、ケイ酸カルシウム、リン酸カルシウム、セルロース、水シロップ、メチルセルロース、ポリビニルピロリドン、アルキルパラヒドロキシベンゾエート、タルク、ステアリン酸、ステアリン酸マグネシウム、寒天、ペクチン、アラビアゴム、グリセリン、ゴマ油、オリーブ油、大豆油カカオバター、エチレングリコール、低粘度ヒドロキシプロピルセルロース（ＨＰＣ－Ｌ）、微結晶セルロース、カルボキシメチルセルロース（ＣＭＣ）、カルボキシメチルセルロースナトリウム（ＣＭＣ－Ｎａ）等やその他常用されるものを挙げることができる。 Additives include commonly used excipients or diluents, and optionally commonly used binders, disintegrants, lubricants, coatings, sugar coatings, pH regulators, solubilizers or aqueous or non-aqueous agents. A solvent can be used. Specifically, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinyl. Pyrrolidone, alkylparahydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil cocoa butter, ethylene glycol, low viscosity hydroxypropyl cellulose (HPC-L), microcrystals Examples thereof include cellulose, carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na) and other commonly used substances.
本発明に係る医薬は、固体組成物、液体組成物及びその他の組成物のいずれの形態でもよく、必要に応じて最適のものが選択される。 The medicine according to the present invention may be in any form of a solid composition, a liquid composition and other compositions, and the optimum one is selected as necessary.
本発明に係る医薬は、本発明の化合物に、前述の添加剤を添加し、常用の製剤技術によって、錠剤、丸剤、カプセル剤、顆粒剤、粉剤、散剤、液剤、乳剤、懸濁剤、注射剤等に調製する事ができる。 The pharmaceutical agent according to the present invention comprises a compound of the present invention to which the above-mentioned additives are added, and tablets, pills, capsules, granules, powders, powders, liquids, emulsions, suspensions, etc. It can be prepared as an injection or the like.
また、本発明に係る医薬は、本発明の化合物と、α、β若しくはγ－シクロデキストリン又はメチル化シクロデキストリン等とで包接化合物を形成させて製剤化することができる。 Further, the pharmaceutical product according to the present invention can be formulated by forming an inclusion compound with the compound of the present invention and α, β or γ-cyclodextrin, methylated cyclodextrin or the like.
本発明に係る医薬は、本発明の化合物と併用可能な化合物について、単一の製剤（配合剤）、又は別々に製剤化して得られる２種以上の製剤（併用剤）とすることができる。
これらの化合物を別々に製剤化して２種以上の製剤とする場合には、個々の製剤を同時又は一定の時間間隔を空けて投与することが可能である。この場合、どちらを先に投与しても構わない。当該２種以上の製剤は、１日にそれぞれ異なる回数で投与することもできる。また、当該２種以上の製剤は、異なる経路で投与することもできる。
The pharmaceutical agent according to the present invention may be a single preparation (combination drug) or two or more kinds of preparations (combination drug) obtained by separately formulating the compound that can be used in combination with the compound of the present invention.
When these compounds are formulated separately to form two or more kinds of formulations, the individual formulations can be administered simultaneously or at regular time intervals. In this case, either may be administered first. The two or more kinds of preparations can be administered at different times a day. In addition, the two or more kinds of formulations can be administered by different routes.
これらの化合物を別々に製剤化して２種の製剤とする場合は、同時に、又は極めて短い間隔で投与する場合もあり、例えば、市販されている医薬の添付文書や販売パンフレット等の文書に、それぞれを併用する旨を記載するのが好ましい。
また、これらの有効成分を別々に製剤化して２種の製剤からなるキットの形態とすることも好ましい。
When these compounds are formulated separately to form two types, they may be administered at the same time or at extremely short intervals, for example, in the package insert of a commercially available drug or a document such as a sales pamphlet, respectively. It is preferable to state that the above is used in combination.
It is also preferable to separately formulate these active ingredients into a kit consisting of two types of preparations.
本発明の化合物を２０－ＨＥＴＥ産生酵素阻害剤などとして使用する場合は、本発明の化合物をそのまま経口投与、又は非経口投与してもよい。また、本発明の化合物を有効成分として含む剤として経口投与、又は非経口投与してもよい。非経口投与としては、静脈内投与、経鼻投与、経皮投与、皮下投与、筋肉内投与、舌下投与があげられる。 When the compound of the present invention is used as a 20-HETE-producing enzyme inhibitor or the like, the compound of the present invention may be orally or parenterally administered as it is. Further, it may be orally or parenterally administered as an agent containing the compound of the present invention as an active ingredient. Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.
本発明の化合物の投与量は、投与対象、投与ルート、対象疾患、症状などによっても異なるが、例えば、成人の患者に経口投与する場合、通常１回量として０．１ｍｇ～１０００ｍｇ、好ましくは１ｍｇ～２００ｍｇであり、この量を、１日に１回～３回、又は２日～３日に１回投与するのが望ましい。 The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc., but for example, when orally administered to an adult patient, the usual single dose is 0.1 mg to 1000 mg, preferably 1 mg. It is ~ 200 mg, and it is desirable to administer this amount once to three times a day or once every two to three days.
本発明の化合物の製剤の製造例を以下に示す。
製剤例１
以下の成分を含有する顆粒剤を製造する。
成分：式［Ｉ］で表される化合物又はその製薬学的に許容される塩、乳糖、コーンスターチ、ＨＰＣ－Ｌ。
式［Ｉ］で表される化合物又はその製薬学的に許容される塩と乳糖をふるいに通す。コーンスターチをふるいに通す。これらを混合機にて混合する。混合末にＨＰＣ－Ｌ水溶液を添加し、練合、造粒（押し出し造粒）した後、乾燥する。得られた乾燥顆粒を振動ふるいで篩過し顆粒剤を得る。
An example of production of a pharmaceutical product of the compound of the present invention is shown below.
Pharmaceutical example 1
Manufacture granules containing the following ingredients.
Ingredients: A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, lactose, cornstarch, HPC-L.
Sift the compound of formula [I] or its pharmaceutically acceptable salt and lactose. Sift the cornstarch through a sieve. These are mixed in a mixer. An HPC-L aqueous solution is added to the mixed powder, kneaded, granulated (extruded granulation), and then dried. The obtained dried granules are sieved with a vibration sieve to obtain granules.
製剤例２
以下の成分を含有するカプセル充填用散剤を製造する。
成分：式［Ｉ］で表される化合物又はその製薬学的に許容される塩、乳糖、コーンスターチ、ステアリン酸マグネシウム。
式［Ｉ］で表される化合物又はその製薬学的に許容される塩と乳糖をふるいに通す。コーンスターチをふるいに通す。これらとステアリン酸マグネシウムを混合機にて混合し、散剤を得る。得られた散剤はカプセルに充填することができる。
Pharmaceutical example 2
Manufacture a capsule filling powder containing the following ingredients.
Ingredients: A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, lactose, cornstarch, magnesium stearate.
Sift the compound of formula [I] or its pharmaceutically acceptable salt and lactose. Sift the cornstarch through a sieve. These and magnesium stearate are mixed in a mixer to obtain a powder. The resulting powder can be filled into capsules.
製剤例３
以下の成分を含有するカプセル充填用顆粒剤を製造する。
成分：式［Ｉ］で表される化合物又はその製薬学的に許容される塩、乳糖、コーンスターチ、ＨＰＣ－Ｌ。
式［Ｉ］で表される化合物又はその製薬学的に許容される塩と乳糖をふるいに通す。コーンスターチをふるいに通す。これらを混合機にて混合する。混合末にＨＰＣ－Ｌ水溶液を添加し、練合、造粒した後、乾燥する。得られた乾燥顆粒を振動ふるいで篩過し整粒し、顆粒を得る。得られた顆粒はカプセルに充填することができる。
Pharmaceutical example 3
Manufacture granules for capsule filling containing the following ingredients.
Ingredients: A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, lactose, cornstarch, HPC-L.
Sift the compound of formula [I] or its pharmaceutically acceptable salt and lactose. Sift the cornstarch through a sieve. These are mixed in a mixer. HPC-L aqueous solution is added to the mixed powder, kneaded, granulated, and then dried. The obtained dried granules are sieved through a vibrating sieve and sized to obtain granules. The resulting granules can be filled into capsules.
製剤例４
以下の成分を含有する錠剤を製造する。
成分：式［Ｉ］で表される化合物又はその製薬学的に許容される塩、乳糖、微結晶セルロース、ステアリン酸マグネシウム、ＣＭＣ－Ｎａ。
式［Ｉ］で表される化合物又はその製薬学的に許容される塩と乳糖と微結晶セルロース、ＣＭＣ－Ｎａをふるいに通し、混合する。混合末にステアリン酸マグネシウムを添加し、製剤用混合末を得る。本混合末を直打し錠剤を得る。
Pharmaceutical example 4
Manufacture tablets containing the following ingredients.
Ingredients: A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, magnesium stearate, CMC-Na.
The compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, and CMC-Na are passed through a sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. Directly hit the mixed powder to obtain tablets.
次に、以下に示す参考例、実施例及び試験例によって本発明をさらに詳細に説明するが、本発明はこれらの内容に限定されるものではなく、また、本発明の範囲を逸脱しない範囲で変化させてもよい。 Next, the present invention will be described in more detail with reference to the following reference examples, examples and test examples, but the present invention is not limited to these contents and does not deviate from the scope of the present invention. It may be changed.
本明細書中で用いられている略語は下記の意味を示す。
ｓ ： シングレット（ｓｉｎｇｌｅｔ）
ｄ ： ダブレット（ｄｏｕｂｌｅｔ）
ｔ ： トリプレット（ｔｒｉｐｌｅｔ）
ｑ ： クァルテット（ｑｕａｒｔｅｔ）
ｑｕｉｎ: クインテット（ｑｕｉｎｔｅｔ）
ｓｘｔ： セクテット（ｓｅｘｔｅｔ）
ｓｐｔ： セプテット（ｓｅｐｔｅｔ）
ｄｄ ： ダブルダブレット（ｄｏｕｂｌｅ ｄｏｕｂｌｅｔ）
ｄｔ ： ダブルトリプレット（ｄｏｕｂｌｅ ｔｒｉｐｌｅｔ）
ｔｄ ： トリプルダブレット（ｔｒｉｐｌｅ ｄｏｕｂｌｅｔ）
ｔｔ ： トリプルトリプレット（ｔｒｉｐｌｅ ｔｒｉｐｌｅｔ）
ｑｄ ： クォーターダブレット（ｑｕａｒｔｅｒ ｄｏｕｂｌｅｔ）
ｍ ： マルチプレット（ｍｕｌｔｉｐｌｅｔ）
ｂｒ ： ブロード（ｂｒｏａｄ）
Ｊ ： カップリング定数（ｃｏｕｐｌｉｎｇ ｃｏｎｓｔａｎｔ）
Ｈｚ ： ヘルツ（Ｈｅｒｔｚ）
ＣＨＬＯＲＯＦＯＲＭ－ｄ : 重クロロホルム
ＤＭＳＯ－ｄ６： 重ジメチルスルホキシド
ＭｅＯＨ－ｄ４ ： 重メタノール
ＡＣＥＴＯＮＥ－ｄ６：重アセトン
Ｄ２Ｏ ： 重水
ｐｏｓｉ ： ｐｏｓｉｔｉｖｅ（ｍｏｄｅ）
ｎｅｇａ ： ｎｅｇａｔｉｖｅ（ｍｏｄｅ）
The abbreviations used herein have the following meanings.
s: singlet
d: Doublet
t: Triplet
q: Quartet
quin: quintet
sxt: sextet
spt: septet
dd: Double doublet
dt: Double triplet
dt: triple doublet
tt: Triple triplet
qd: Quarter doublet
m: Multiplet
br: Broad
J: Coupling constant
Hz: Hertz
CHLOROFORM-d: Deuterated chloroform DMSO-d 6 : Deuterated dimethyl sulfoxide MeOH-d 4 : Deuterated methanol ACETONE-d 6 : Deuterated acetone D 2 O: Heavy water pose: positive (mode)
nega: negative (mode)
ＴＨＰ： テトラヒドロピラニル
ＴＭＳ： トリメチルシリル
THP: Tetrahydropyranyl TMS: Trimethylsilyl
Ｒｆ ： 遅延係数（ｒｅｔａｒｄａｔｉｏｎ ｆａｃｔｏｒ） Rf: Delay coefficient (retention factor)
１Ｈ－ＮＭＲ（プロトン核磁気共鳴スペクトル）は、内部標準としてテトラメチルシランを用いて下記のフーリエ変換型ＮＭＲで測定し、全δ値をｐｐｍで示した。
２００ＭＨｚ： Ｇｅｍｉｎｉ２０００ （Ａｇｉｌｅｎｔ Ｔｅｃｈｎｏｌｏｇｉｅｓ）
３００ＭＨｚ： Ｉｎｏｖａ３００ （Ａｇｉｌｅｎｔ Ｔｅｃｈｎｏｌｏｇｉｅｓ）
４００ＭＨｚ： ＡＶＡＮＣＥ III ＨＤ４００ （Ｂｒｕｋｅｒ）
５００ＭＨｚ： ＪＮＭ－ＥＣＡ５００ （ＪＥＯＬ）
６００ＭＨｚ： ＪＮＭ－ＥＣＡ６００ （ＪＥＯＬ）
1 H-NMR (proton nuclear magnetic resonance spectrum) was measured by the following Fourier transform type NMR using tetramethylsilane as an internal standard, and the total δ value was shown in ppm.
200MHz: Gemini2000 (Agilent Technologies)
300MHz: Inova300 (Agilent Technologies)
400MHz: AVANCE III HD400 (Bruker)
500MHz: JNM-ECA500 (JEOL)
600MHz: JNM-ECA600 (JEOL)
解析にはＡＣＤ／Ｓｐｅｃｔｒｕｓ Ｐｒｏｃｅｓｓｏｒ ２０１７．１．３ ＡＣＤ／Ｌａｂｓ ２０１７．１．３ Ｒｅｌｅａｓｅ（Ｆｉｌｅ Ｖｅｒｓｉｏｎ Ｓ７０Ｓ４１， Ｂｕｉｌｄ ９７０２７， ２７ Ｓｅｐ ２０１７）（商品名）などを用いた。ヒドロキシやアミノ、アミド、ピラゾールなどのプロトンが非常に緩やかなピークについては記載していないこともある。
なお、化合物の解析において、水又は溶媒のピークと重なって同定できていないプロトンが存在する場合もある。
For the analysis, ACD / Spectrus Procedure 2017.1.3 ACD / Labs 2017.1.3 Release (File Version S70S41, Build 97027, 27 Sep 2017) (trade name) and the like were used. It may not mention peaks with very gradual protons such as hydroxy, amino, amides and pyrazoles.
In the analysis of the compound, there may be a proton that cannot be identified because it overlaps with the peak of water or solvent.
ＭＳ（マススペクトル）は以下の装置にて測定した。
ＰｌａｔｆｏｒｍＬＣ （Ｗａｔｅｒｓ）
ＬＣＭＳ－２０１０ＥＶ （Ｓｈｉｍａｄｚｕ）
ＬＣＭＳ－ＩＴ－ＴＯＦ （Ｓｈｉｍａｄｚｕ）
Ａｇｉｌｅｎｔ６１３０ （Ａｇｉｌｅｎｔ）
Ａｇｉｌｅｎｔ６１５０ （Ａｇｉｌｅｎｔ）
イオン化法としては、ＥＳＩ（Ｅｌｅｃｔｒｏｓｐｒａｙ Ｉｏｎｉｚａｔｉｏｎ、エレクトロスプレーイオン化）法、ＥＩ（Ｅｌｅｃｔｒｏｎ Ｉｏｎｉｚａｔｉｏｎ、電子イオン化法）、又は、ＥＳＩ及びＡＰＣＩ（Ａｔｍｏｓｐｈｅｒｉｃ Ｐｒｅｓｓｕｒｅ Ｃｈｅｍｉｃａｌ Ｉｏｎｉｚａｔｉｏｎ、大気圧化学イオン化）法とのデュアルイオン化法を用いた。データは実測値（ｆｏｕｎｄ）を記載した。通常、分子イオンピークが観測されるが、ｔｅｒｔ－ブトキシカルボニル（－Ｂｏｃ）を有する化合物の場合、フラグメントイオンとして、ｔｅｒｔ－ブトキシカルボニル或いはｔｅｒｔ－ブチルが脱離したピークが観測されることもある。また、テトラヒドロピラニル（ＴＨＰ）を有する化合物の場合、フラグメントイオンとして、テトラヒドロピラニルが脱離したピークが観測されることもある。また、ヒドロキシ（－ＯＨ）を有する化合物の場合、フラグメントピークとしてＨ２ＯやＯＨラジカルが脱離したピークが観測されることもある。塩の場合は、通常、フリー体の分子イオンピーク若しくはフラグメントイオンピークが観測される。
MS (mass spectrum) was measured with the following equipment.
PlatformLC (Waters)
LCMS-2010EV (Shimadzu)
LCMS-IT-TOF (Shimadzu)
Agilent 6130 (Agilent)
Agilent 6150 (Agilent)
As the ionization method, ESI (Electrospray Ionization, electrospray ionization) method, EI (Electrospray Ionization, electron ionization method), or ESI and APCI (Atmospheric Pressure Chemical Ionization) dual method for atmospheric pressure chemical ionization. board. For the data, the measured value (found) is described. Normally, a molecular ion peak is observed, but in the case of a compound having tert-butoxycarbonyl (-Boc), a peak in which tert-butoxycarbonyl or tert-butyl is desorbed may be observed as a fragment ion. Further, in the case of a compound having tetrahydropyranyl (THP), a peak in which tetrahydropyranyl is eliminated may be observed as a fragment ion. Further, in the case of a compound having hydroxy (-OH), a peak in which H2O or OH radical is eliminated may be observed as a fragment peak. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.
実施例、参考例におけるＬＣ－ＭＳは以下の条件により測定した。
ＨＰＬＣ：Ａｇｉｌｅｎｔ １２９０ Ｉｎｆｉｎｉｔｙ
ＭＳ：Ａｇｉｌｅｎｔ ６１３０ 又は ６１５０
［ＨＰＬＣ条件］
カラム：Ａｃｑｕｉｔｙ ＵＰＬＣ ＣＳＨ Ｃ１８、１．７μｍ、２．１ｘ×５０ｍｍ（ＷＡＴＥＲＳ）
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
LC-MS in Examples and Reference Examples was measured under the following conditions.
HPLC: Agilent 1290 Infinity
MS: Agilent 6130 or 6150
[HPLC conditions]
Column: Accuracy UPLC CSH C18, 1.7 μm, 2.1x × 50 mm (WATERS)
Solvent: Solution A; 0.1% formic acid-containing water, Solution B; 0.1% formic acid-containing acetonitrile
（方法Ａ）
グラジエント：０．００分（Ａ液／Ｂ液＝８０／２０）、１．２０分（Ａ液／Ｂ液＝１／９９）、１．４０分（Ａ液／Ｂ液＝１／９９）、１．４１分（Ａ液／Ｂ液＝８０／２０）、１．５０分（Ａ液／Ｂ液＝８０／２０）
（方法Ｂ）
グラジエント：０．００分（Ａ液／Ｂ液＝９５／５）、０．８０分（Ａ液／Ｂ液＝６０／４０）、１．０８分（Ａ液／Ｂ液＝１／９９）、１．３８分（Ａ液／Ｂ液＝１／９９）、１．４１分（Ａ液／Ｂ液＝９５／５）、１．５０分（Ａ液／Ｂ液＝８０／２０）
（方法Ｃ）
グラジエント：０．００分（Ａ液／Ｂ液＝７０／３０）、０．８０分（Ａ液／Ｂ液＝１／９９）、１．４０分（Ａ液／Ｂ液＝１／９９）、１．４２分（Ａ液／Ｂ液＝７０／３０）、１．５０分（Ａ液／Ｂ液＝７０／３０）
(Method A)
Radiant: 0.00 minutes (Liquid A / Liquid B = 80/20), 1.20 minutes (Liquid A / Liquid B = 1/99), 1.40 minutes (Liquid A / Liquid B = 1/99), 1.41 minutes (Liquid A / Liquid B = 80/20), 1.50 minutes (Liquid A / Liquid B = 80/20)
(Method B)
Radiant: 0.00 minutes (Liquid A / Liquid B = 95/5), 0.80 minutes (Liquid A / Liquid B = 60/40), 1.08 minutes (Liquid A / Liquid B = 1/99), 1.38 minutes (Liquid A / Liquid B = 1/99), 1.41 minutes (Liquid A / Liquid B = 95/5), 1.50 minutes (Liquid A / Liquid B = 80/20)
(Method C)
Radiant: 0.00 minutes (Liquid A / Liquid B = 70/30), 0.80 minutes (Liquid A / Liquid B = 1/99), 1.40 minutes (Liquid A / Liquid B = 1/99), 1.42 minutes (Liquid A / Liquid B = 70/30), 1.50 minutes (Liquid A / Liquid B = 70/30)
注入量：０．５μＬ、流速：０．８ｍＬ／ｍｉｎ
検出法：ＵＶ２１０ｎｍ、２５４ｎｍ
蒸発光散乱検出器（ＥＬＳＤ）が付属する場合 Ａｇｉｌｅｎｔ ３８５－ＥＬＳＤ
ＭＳ条件
イオン化法：ＥＳＩ 又は ＥＳＩ／ＡＰＣＩマルチモード
Injection volume: 0.5 μL, flow rate: 0.8 mL / min
Detection method: UV210nm, 254nm
When Evaporative Light Scattering Detector (ELSD) is attached Agilent 385-ELSD
MS condition Ionization method: ESI or ESI / APCI multimode
実施例、参考例における分取ＨＰＬＣによる精製は以下の条件により行った。
機器：ギルソン社ハイスループット精製システム
カラム：Ｔｒｉａｒｔ Ｃ１８、５μｍ、３０×５０ｍｍ（ＹＭＣ）、又はＸ－Ｂｒｉｄｇｅ Ｐｒｅｐ Ｃ１８ ５ｕｍ ＯＢＤ、３０ｘ５０（Ｗａｔｅｒｓ）
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
Purification by preparative HPLC in Examples and Reference Examples was performed under the following conditions.
Instrument: Gilson High Throughput Purification System Column: Triart C18, 5 μm, 30 × 50 mm (YMC), or X-Bridge Prep C18 5um OBD, 30x50 (Waters)
Solvent: Solution A; 0.1% formic acid-containing water, Solution B; 0.1% formic acid-containing acetonitrile
グラジエント：０．００分（Ａ液／Ｂ液＝９０／１０）、２．００分（Ａ液／Ｂ液＝９０／１０）、１１．０分（Ａ液／Ｂ液＝２０／８０）、１２．０分（Ａ液／Ｂ液＝５／９５）、１３．５２分（Ａ液／Ｂ液＝５／９５）、１５．０分（Ａ液／Ｂ液＝９０／１０） Radiant: 0.00 minutes (Liquid A / Liquid B = 90/10), 2.00 minutes (Liquid A / Liquid B = 90/10), 11.0 minutes (Liquid A / Liquid B = 20/80), 12.0 minutes (Liquid A / Liquid B = 5/95), 13.52 minutes (Liquid A / Liquid B = 5/95), 15.0 minutes (Liquid A / Liquid B = 90/10)
流速：４０ｍＬ/ｍｉｎ
検出法：ＵＶ２５４ｎｍ
Flow rate: 40 mL / min
Detection method: UV254nm
化合物の融点は株式会社リガク製熱重量示差熱分析装置Ｔｈｅｒｍｏ Ｐｌｕｓ Ｅｖｏ ＴＧ８１２０を用い、示差熱・熱重量測定（ＴＧ－ＤＴＡ）法により測定した。 The melting point of the compound was measured by a differential thermal / thermal weight measurement (TG-DTA) method using a thermal weight differential thermal analyzer Thermo Plus Evo TG8120 manufactured by Rigaku Corporation.
フェーズセパレーターは、バイオタージ社のＩＳＯＬＵＴＥ（登録商標） Ｐｈａｓｅ Ｓｅｐａｒａｔｏｒを用いた。 As the phase separator, ISOLUTE (registered trademark) Phase Separator manufactured by Biotage was used.
化合物名はＯｐｅｎｅｙｅ社製、ＰｉｐｅｌｉｎｅＰｉｌｏｔ９．５のコンポーネント、Ｍｏｌｅｃｕｌａｒ ｔｏ Ｃｈｅｍｉｃａｌ Ｎａｍｅ（ｖｅｒｓｉｏｎ １）により命名した。 The compound was named by Molecular to Chemical Name (version 1), a component of Pipeline Pilot 9.5 manufactured by Openeye.
本明細書では、室温とは２０℃～３０℃を指す。
氷冷下とは０℃～５℃を指す。
As used herein, room temperature refers to 20 ° C to 30 ° C.
Under ice cooling means 0 ° C to 5 ° C.
参考例１
６－（１，２，４－トリアゾル－１－イル）ピリジン－３－オール
Reference example 1
6- (1,2,4-triazol-1-yl) Pyridine-3-ol
（２）上記（１）で得られた化合物（２３．１ｇ）、１，２，４－トリアゾール（９．０７ｇ）、トランス－Ｎ，Ｎ’－ジメチルシクロヘキサン－１，２－ジアミン（２２．１ｍＬ）、水酸化カリウム（１０．３ｇ）、アセトニトリル（１８５ｍＬ）、及び水（１５．８ｍＬ）の混合物へ、窒素雰囲気下ヨウ化銅（３．３４ｇ）加え、９５℃で１０時間撹拌した。混合物を室温まで冷却し、減圧下濃縮した。残渣にクロロホルム及び水を加えて撹拌し、不溶物を濾別した。有機層を分離し水層をクロロホルムで抽出した。合わせた有機層をフェーズセパレーターに通し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９７：３）にて精製した。得られた粗生成物をｎ－ヘキサン：エタノール＝２：１混合液中、室温にて２日間撹拌した。析出した固体を濾取し、ｎ－ヘキサン：エタノール＝４：１混合液で洗浄した。濾取物を通気乾燥し５－フェニルメトキシ－２－（１，２，４－トリアゾル－１－イル）ピリジン（１８．９ｇ）を淡黄色固体として得た。
（３）上記（２）で得られた化合物（１８．９ｇ）のメタノール（２４９ｍＬ）懸濁液へ５％パラジウム炭素（１．８９ｇ）を加え、水素雰囲気下、室温にて２０時間撹拌した。反応系を窒素置換し５０℃にて３０分間撹拌した。室温まで冷却した後、触媒を濾別しテトラヒドロフランにて洗浄した。濾液を減圧下濃縮し、得られた残渣にｎ－ヘキサン：エタノール＝３：２混合液を加え、室温にて一晩撹拌した。析出した固体を濾取、ｎ－ヘキサン：エタノール＝３：２混合液で洗浄し、減圧下乾燥し標題化合物（１１．６ｇ）を淡灰色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ ppm 7.39 - 7.49 (m, 1 H) 7.71 (d, J=8.4 Hz, 1 H) 8.05 (s, 1 H) 8.22 (s, 1 H) 9.19 (s, 1 H) 10.34 (br s, 1 H).
MS ESI posi: 163[M+H]+.
MS ESI nega: 161[M-H]-.
参考例２
３－（８－ヒドロキシオクチル）オキセタン－３－カルボン酸メチル
(2) The compound (23.1 g) obtained in (1) above, 1,2,4-triazole (9.07 g), trans-N, N'-dimethylcyclohexane-1,2-diamine (22.1 mL). ), Potassium hydroxide (10.3 g), acetonitrile (185 mL), and water (15.8 mL) were added with copper iodide (3.34 g) under a nitrogen atmosphere, and the mixture was stirred at 95 ° C. for 10 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Chloroform and water were added to the residue, and the mixture was stirred and the insoluble material was filtered off. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3). The obtained crude product was stirred in a mixed solution of n-hexane: ethanol = 2: 1 at room temperature for 2 days. The precipitated solid was collected by filtration and washed with a mixed solution of n-hexane: ethanol = 4: 1. The sample was aerated and dried to obtain 5-phenylmethoxy-2- (1,2,4-triazol-1-yl) pyridine (18.9 g) as a pale yellow solid.
(3) 5% palladium carbon (1.89 g) was added to a methanol (249 mL) suspension of the compound (18.9 g) obtained in (2) above, and the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. The reaction system was replaced with nitrogen and stirred at 50 ° C. for 30 minutes. After cooling to room temperature, the catalyst was filtered off and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, an n-hexane: ethanol = 3: 2 mixture was added to the obtained residue, and the mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration, washed with a mixture of n-hexane: ethanol = 3: 2, and dried under reduced pressure to give the title compound (11.6 g) as a light gray solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.39 --7.49 (m, 1 H) 7.71 (d, J = 8.4 Hz, 1 H) 8.05 (s, 1 H) 8.22 (s, 1 H) 9.19 (s, 1 H) 10.34 (br s, 1 H).
MS ESI posi: 163 [M + H] + .
MS ESI nega: 161 [MH] -- .
Reference example 2
Methyl 3- (8-hydroxyoctyl) oxetane-3-carboxylate
（２）上記（１）で得られた混合物（１００ｍｇ）のメタノール（１．５ｍＬ）及び水（０．５ｍＬ）溶液へ、氷冷下トリフルオロ酢酸（０．２５ｍＬ）を加え、室温にて２時間撹拌した。混合物へ飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層をフェーズセパレーターに通し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル＝９２：８～３０：７０）にて精製し、標題化合物（６５ｍｇ）を無色油状物質として得た。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 - 1.40 (m, 12 H) 1.94 - 2.02 (m, 2 H) 3.64 (t, J=6.6 Hz, 2 H) 3.76 (s, 3 H) 4.43 (d, J=6.1 Hz, 2 H) 4.89 (d, J=6.1 Hz, 2 H).
MS ESI posi: 245[M+H]+.
参考例３
３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸
(2) Add trifluoroacetic acid (0.25 mL) under ice-cooling to a solution of the mixture (100 mg) obtained in (1) above in methanol (1.5 mL) and water (0.5 mL), and add 2 at room temperature. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 92: 8 to 30:70) to give the title compound (65 mg) as a colorless oily substance.
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 --1.40 (m, 12 H) 1.94 --2.02 (m, 2 H) 3.64 (t, J = 6.6 Hz, 2 H) 3.76 (s, 3 H) 4.43 (d, J = 6.1 Hz, 2 H) 4.89 (d, J = 6.1 Hz, 2 H).
MS ESI posi: 245 [M + H] + .
Reference example 3
3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid
（２）上記（１）で得られた混合物（１４０ｍｇ）をメタノール（１．８ｍＬ）に懸濁し、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（３８７μＬ）を加え、室温にて一晩撹拌した。混合物を分取ＨＰＬＣにより精製した。目的物を含むフラクションを濃縮して、標題化合物を固体として得た。
実施例１
３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸
(2) The mixture (140 mg) obtained in (1) above was suspended in methanol (1.8 mL), a 1 mol / L sodium hydroxide aqueous solution (387 μL) was added, and the mixture was stirred overnight at room temperature. The mixture was purified by preparative HPLC. Fractions containing the desired product were concentrated to give the title compound as a solid.
Example 1
3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 - 1.47 (m, 10 H) 1.70 - 1.79 (m, 2 H) 1.85 - 1.93 (m, 2 H) 4.10 (t, J=6.4 Hz, 2 H) 4.32 (d, J=5.9 Hz, 2 H) 4.68 (d, J=5.9 Hz, 2 H) 7.67 (dd, J=8.9, 2.7 Hz, 1 H) 7.80 (d, J=8.9 Hz, 1 H) 8.23 (d, J=2.7 Hz, 1 H) 8.25 (s, 1 H) 9.24 (s, 1 H).
MS ESI posi: 375[M+H]+.
MS ESI nega: 373[M-H]-.
実施例２
３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸（Ａ形結晶）
1 H NMR (400 MHz, DMSO-d6) δ ppm 1.13 --1.47 (m, 10 H) 1.70 --1.79 (m, 2 H) 1.85 --1.93 (m, 2 H) 4.10 (t, J = 6.4 Hz, 2) H) 4.32 (d, J = 5.9 Hz, 2 H) 4.68 (d, J = 5.9 Hz, 2 H) 7.67 (dd, J = 8.9, 2.7 Hz, 1 H) 7.80 (d, J = 8.9 Hz, 1) H) 8.23 (d, J = 2.7 Hz, 1 H) 8.25 (s, 1 H) 9.24 (s, 1 H).
MS ESI posi: 375 [M + H] + .
MS ESI nega: 373 [MH] -- .
Example 2
3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid (A-type crystal)
上記固体の粉末Ｘ線回折パターン及び示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）を測定したところ、Ａ形結晶であった。
粉末Ｘ線回折パターンについては、２θ＝４．７度、１４．１度、１７．５度、及び１８．９度にピークが認められた。
示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）については、１２３℃に吸熱ピークが認められた。
実施例３
３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸（Ａ形結晶）
When the powder X-ray diffraction pattern of the solid and the differential thermal analysis / thermogravimetric analysis (TG / DTA) were measured, it was an A-type crystal.
For the powder X-ray diffraction pattern, peaks were observed at 2θ = 4.7 degrees, 14.1 degrees, 17.5 degrees, and 18.9 degrees.
For differential thermal analysis / thermal mass measurement (TG / DTA), an endothermic peak was observed at 123 ° C.
Example 3
3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid (A-type crystal)
上記固体の粉末Ｘ線回折パターンを測定したところ、Ａ形結晶であった。
When the powder X-ray diffraction pattern of the solid was measured, it was an A-type crystal.
以下の実施例４～６では、３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸の粗生成物へ下記表１に示す各種溶媒を加え、実施例３に記載の方法又はこれに準じる方法にて再結晶を行った。なお、再結晶における加熱温度としては、外温である油浴の温度が６５℃～８５℃であった。
表１に、各実施例における、再結晶に使用した溶媒を示す。
In the following Examples 4 to 6, to the crude product of 3- [8- [6- (1,2,4-triazol-1-yl) pyridine-3-yl] oxyoctyl] oxetane-3-carboxylic acid. Various solvents shown in Table 1 below were added, and recrystallization was performed by the method described in Example 3 or a method similar thereto. As the heating temperature for recrystallization, the temperature of the oil bath, which is the outside temperature, was 65 ° C to 85 ° C.
Table 1 shows the solvent used for recrystallization in each example.
上記各実施例において得られた固体の粉末Ｘ線回折パターンを測定したところ、いずれもＡ形結晶であった。
When the powder X-ray diffraction pattern of the solid obtained in each of the above Examples was measured, all of them were A-type crystals.
本発明化合物の２０－ＨＥＴＥ産生酵素の阻害作用を、以下の試験例１に記載した方法により測定した。 The inhibitory effect of the 20-HETE-producing enzyme of the compound of the present invention was measured by the method described in Test Example 1 below.
試験例１
（１）本発明化合物の、２０－ＨＥＴＥ産生酵素（ＣＹＰ４Ｆ２及びＣＹＰ４Ａ１１）の阻害試験
ＣＹＰ４Ｆ２阻害試験ではヒトＣＹＰ４Ｆ２を発現させた大腸菌膜画分（１００μｇ／ｍＬ ｐｒｏｔｅｉｎ）に、化合物を含む反応液［最終濃度 ５０ｍＭ ＫＰＯ4（ｐＨ７．４）、２．５μＭ ルシフェリン誘導体、及び１ｍＭ ＮＡＤＰＨ］を添加後、ＣＹＰ４Ａ１１阻害試験ではヒトＣＹＰ４Ａ１１を発現させた大腸菌膜画分（１００μｇ／ｍＬ ｐｒｏｔｅｉｎ）に、化合物を含む反応液［最終濃度 １００ｍＭ Ｔｒｉｓ－ＨＣｌ（ｐＨ７．５）、６０μＭ ルシフェリン誘導体、１．３ｍＭ ＮＡＤＰ+、３．３ｍＭ Ｇｌｕｃｏｓｅ ６－Ｐｈｏｓｐｈａｔｅ、３．３ｍＭ ＭｇＣｌ２、及び０．４Ｕ／ｍＬ Ｇｌｕｃｏｓｅ ６－Ｐｈｏｓｐｈａｔｅ ｄｅｈｙｄｒｏｇｅｎａｓｅ］を添加後、室温で６０分間静置し、酵素反応を行った。反応後にルシフェリン検出試薬を添加し、プレートリーダーを用いて発光値を測定した。その値を用いて２０－ＨＥＴＥ産生酵素阻害率（％）を下記の式に従って算出し、化合物の５０％阻害濃度（ＩＣ５０値）を算出した。
２０－ＨＥＴＥ産生酵素阻害率（％）=［１－（Ａ－Ｂ）/（Ｃ－Ｂ）］＊１００
Ａ: 化合物添加時の発光値
Ｂ: 化合物及び酵素非添加時の発光値
Ｃ: 化合物非添加時の発光値
Test Example 1
(1) Inhibition test of 20-HETE-producing enzymes (CYP4F2 and CYP4A11) of the compound of the present invention In the CYP4F2 inhibition test, a reaction solution containing the compound in the E. coli membrane fraction (100 μg / mL protein) expressing human CYP4F2 [final After adding 50 mM KPO 4 (pH 7.4), 2.5 μM luciferin derivative, and 1 mM NADPH], the reaction containing the compound in the E. coli membrane fraction (100 μg / mL protein) expressing human CYP4A11 in the CYP4A11 inhibition test. Liquid [final concentration 100 mM Tris-HCl (pH 7.5), 60 μM luciferin derivative, 1.3 mM NADP + , 3.3 mM Glucose 6-Phosphate, 3.3 mM MgCl 2 , and 0.4 U / mL Glucose 6-Phosphate dehydrogenase] Was added, and the mixture was allowed to stand at room temperature for 60 minutes for an enzymatic reaction. After the reaction, a luciferin detection reagent was added, and the luminescence value was measured using a plate reader. Using that value, the 20-HETE-producing enzyme inhibition rate (%) was calculated according to the following formula, and the 50% inhibition concentration ( IC50 value) of the compound was calculated.
20-HETE-producing enzyme inhibition rate (%) = [1- (AB) / (CB)] * 100
A: Luminescence value when compound is added B: Luminescence value when compound and enzyme are not added C: Luminescence value when compound is not added
（２）結果
本発明化合物のＣＹＰ４Ｆ２及びＣＹＰ４Ａ１１に対する阻害活性を以下の表２に示す。
(2) Results The inhibitory activity of the compound of the present invention against CYP4F2 and CYP4A11 is shown in Table 2 below.
また、本発明化合物の２０－ＨＥＴＥを産生する酵素を阻害する作用を、以下の試験例２に記載した方法によっても測定した。 In addition, the action of the compound of the present invention to inhibit the enzyme that produces 20-HETE was also measured by the method described in Test Example 2 below.
試験例２
（１）本発明化合物の、ヒト腎ミクロソームを使用した２０－ＨＥＴＥ産生酵素の阻害試験
ヒト腎ミクロソーム（２５０μｇ／ｍＬ ｐｒｏｔｅｉｎ）に、化合物を含む反応液［最終濃度 １００ｍＭ ＫＰＯ４（ｐＨ７．４）、２０μＭ Ａｒａｃｈｉｄｏｎｉｃ ａｃｉｄ、４ｍＭ ＮＡＤＰＨ］を添加後、３７℃で４５分間静置し、２０－ＨＥＴＥ産生反応を行った。ギ酸を添加して反応を停止した後、９倍量のアセトニトリルを添加し、遠心（１０００ｒｐｍ、４℃、１０分）により除タンパクを行った。その後、液体クロマトグラフ－タンデム型質量分析装置（ＬＣ－ＭＳ／ＭＳ）を用いて２０－ＨＥＴＥのピーク面積値を測定し、その値を用いて２０－ＨＥＴＥ産生酵素阻害率（％）を下記の式に従って算出し、化合物の５０％阻害濃度（ＩＣ５０値）を算出した。
２０－ＨＥＴＥ産生酵素阻害率（％）＝［１－（Ａ－Ｂ）／（Ｃ－Ｂ）］＊１００
Ａ： 化合物添加時の２０－ＨＥＴＥのピーク面積値／内部標準物質のピーク面積値
Ｂ： 化合物及びＮＡＤＰＨ非添加時の
２０－ＨＥＴＥのピーク面積値／内部標準物質のピーク面積値
Ｃ： 化合物非添加時の２０－ＨＥＴＥのピーク面積値／内部標準物質のピーク面積値
Test Example 2
(1) Inhibition test of 20-HETE-producing enzyme of the compound of the present invention using human renal microsomes A reaction solution containing the compound in human renal microsomes (250 μg / mL protein) [final concentration 100 mM KPO 4 (pH 7.4), 20 μM Arachidonic acid, 4 mM NADPH] was added, and the mixture was allowed to stand at 37 ° C. for 45 minutes to carry out a 20-HETE production reaction. After adding formic acid to stop the reaction, 9 times the amount of acetonitrile was added, and deproteinization was performed by centrifugation (1000 rpm, 4 ° C., 10 minutes). Then, the peak area value of 20-HETE was measured using a liquid chromatograph-tandem mass spectrometer (LC-MS / MS), and the value was used to determine the 20-HETE-producing enzyme inhibition rate (%) as follows. It was calculated according to the formula, and the 50% inhibitory concentration ( IC50 value) of the compound was calculated.
20-HETE-producing enzyme inhibition rate (%) = [1- (AB) / (CB)] * 100
A: Peak area value of 20-HETE when compound is added / Peak area value of internal standard substance B: Peak area value of 20-HETE when compound and NADPH are not added / Peak area value of internal standard substance C: No compound added Peak area value of 20-HETE at time / Peak area value of internal standard substance
（２）結果
本発明化合物の２０－ＨＥＴＥ産生酵素に対する阻害活性を、以下の表３に示す。
(2) Results The inhibitory activity of the compound of the present invention on the 20-HETE-producing enzyme is shown in Table 3 below.
試験例３ 本発明化合物の、ＣＹＰ選択性試験
（１）本発明化合物の、ＣＹＰ４Ｆ２２選択性試験
ヒトＣＹＰ４Ｆ２２を発現させた細胞膜画分（３０μｇ／ｍＬ ｐｒｏｔｅｉｎ）に、化合物を含む反応液［最終濃度 １００ｍＭ ＫＰＯ4（ｐＨ７．４）、１４μＭ ルシフェリン誘導体、及び１ｍＭ ＮＡＤＰＨ］を添加後、室温で５０分間静置し、酵素反応を行った。反応後にルシフェリン検出試薬を添加し、プレートリーダーを用いて発光値を測定した。その値を用いてＣＹＰ４Ｆ２２の酵素反応阻害率（％）を下記の式に従って算出し、化合物の５０％阻害濃度（ＩＣ５０値）を算出した。
ＣＹＰ４Ｆ２２酵素阻害率（％）=［１－（Ａ－Ｂ）/（Ｃ－Ｂ）］＊１００
Ａ: 化合物添加時の発光値
Ｂ: 化合物及び酵素非添加時の発光値
Ｃ: 化合物非添加時の発光値
（２）結果
本発明化合物のＣＹＰ４Ｆ２２に対する阻害活性を、以下の表４－１に示す
Test Example 3 CYP selectivity test of the compound of the present invention (1) CYP4F22 selectivity test of the compound of the present invention A reaction solution containing the compound in the cell membrane fraction (30 μg / mL protein) expressing the human CYP4F22 [final concentration 100 mM] After adding KPO 4 (pH 7.4), 14 μM luciferin derivative, and 1 mM NADPH], the mixture was allowed to stand at room temperature for 50 minutes for an enzymatic reaction. After the reaction, a luciferin detection reagent was added, and the luminescence value was measured using a plate reader. Using that value, the enzyme reaction inhibition rate (%) of CYP4F22 was calculated according to the following formula, and the 50% inhibition concentration (IC 50 value) of the compound was calculated.
CYP4F22 enzyme inhibition rate (%) = [1- (AB) / (CB)] * 100
A: Luminescence value when compound is added B: Luminescence value when compound and enzyme are not added C: Luminescence value when compound is not added (2) Results The inhibitory activity of the compound of the present invention against CYP4F22 is shown in Table 4-1 below.
（３）本発明化合物の、ＣＹＰ４Ｖ２選択性試験
ヒトＣＹＰ４Ｖ２を発現させた細胞膜画分（３８μｇ／ｍＬ ｐｒｏｔｅｉｎ）に、化合物を含む反応液［最終濃度 １００ｍＭ ＫＰＯ4（ｐＨ７．４）、７μＭ ルシフェリン誘導体、及び１ｍＭ ＮＡＤＰＨ］を添加後、室温で４０分間静置し、酵素反応を行った。反応後にルシフェリン検出試薬を添加し、プレートリーダーを用いて発光値を測定した。その値を用いてＣＹＰ４Ｖ２の酵素反応阻害率（％）を下記の式に従って算出し、化合物の５０％阻害濃度（ＩＣ５０値）を算出した。
ＣＹＰ４Ｖ２酵素阻害率（％）=［１－（Ａ－Ｂ）/（Ｃ－Ｂ）］＊１００
Ａ: 化合物添加時の発光値
Ｂ: 化合物及び酵素非添加時の発光値
Ｃ: 化合物非添加時の発光値
（４）結果
本発明化合物のＣＹＰ４Ｖ２に対する阻害活性を、以下の表４－２に示す
(3) CYP4V2 selectivity test of the compound of the present invention A reaction solution containing the compound in the cell membrane fraction (38 μg / mL protein) expressing human CYP4V2 [final concentration 100 mM KPO 4 (pH 7.4), 7 μM luciferin derivative, And 1 mM NADPH], the mixture was allowed to stand at room temperature for 40 minutes, and an enzymatic reaction was carried out. After the reaction, a luciferin detection reagent was added, and the luminescence value was measured using a plate reader. Using the value, the enzyme reaction inhibition rate (%) of CYP4V2 was calculated according to the following formula, and the 50% inhibition concentration (IC 50 value) of the compound was calculated.
CYP4V2 enzyme inhibition rate (%) = [1- (AB) / (CB)] * 100
A: Luminescence value when compound is added B: Luminescence value when compound and enzyme are not added C: Luminescence value when compound is not added (4) Results The inhibitory activity of the compound of the present invention against CYP4V2 is shown in Table 4-2 below.
なお、同様の方法で、化合物の９０％阻害濃度（ＩＣ９０値）も算出できる。場合によっては、９０％阻害濃度を指標にした方が望ましい場合がある。 The 90% inhibitory concentration (IC 90 value) of the compound can also be calculated by the same method. In some cases, it may be desirable to use the 90% inhibitory concentration as an index.
試験例４
（１）本発明化合物の、体内安定性の評価試験
以下の方法に従って、血漿中半減期を算出することができる。
化合物を１０％ＨＰ－β－ＣＤ水溶液に溶解し（０．５ｍｇ／ｍＬ）、ラット（Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙ（ＳＤ）、雄、７週齢、絶食、投与量：０．５ｍｇ／ｋｇ）に静脈内投与する。各採血時間に尾静脈より採血し、遠心分離により血漿を採取する。血漿中の化合物の定量分析はＬＣ－ＭＳ／ＭＳを用いて実施する。血漿中半減期（ｔ１／２ｅｆｆ）はＰｈｏｅｎｉｘ ＷｉｎＮｏｎｌｉｎ（Cｅｒｔａｒａ）を用い、ノンコンパートメント解析により算出したクリアランス（ＣＬ）及び分布容積（Ｖｄｓｓ）から下記の式に従って算出できる。
ｔ１／２ｅｆｆ＝ＬＮ（２）／（ＣＬ／Ｖｄｓｓ）
Test Example 4
(1) Evaluation test of internal stability of the compound of the present invention The plasma half-life can be calculated according to the following method.
The compound was dissolved in a 10% HP-β-CD aqueous solution (0.5 mg / mL) and intravenously in rats (Sprague-Dawley (SD), male, 7 weeks old, fasting, dose: 0.5 mg / kg). Administer. Blood is collected from the tail vein at each blood collection time, and plasma is collected by centrifugation. Quantitative analysis of compounds in plasma is performed using LC-MS / MS. The half-life in plasma (t 1 / 2eff ) can be calculated according to the following formula from the clearance (CL) and volume of distribution ( Vdss ) calculated by non-compartment analysis using Phoenix WinNonlin (Certara).
t 1 / 2eff = LN (2) / (CL / Vds ss )
さて、本発明化合物は、２０－ＨＥＴＥ産生酵素（ＣＹＰ４Ｆ２及びＣＹＰ４Ａ１１）と同じファミリーであるＣＹＰ４Ｆ２２、ＣＹＰ４Ｖ２よりもＣＹＰ４Ｆ２及びＣＹＰ４Ａ１１に対して高い選択性を有する。
本発明化合物は、強力な薬効を有しながらかつ副作用リスクの小さい医薬品として提供されることが、期待される。
Now, the compound of the present invention has higher selectivity for CYP4F2 and CYP4A11 than CYP4F22, CYP4V2, which are the same family as the 20-HETE producing enzymes (CYP4F2 and CYP4A11).
The compound of the present invention is expected to be provided as a drug having a strong medicinal effect and a low risk of side effects.
また、本発明化合物の有効性は、マウスやラット等のモデル動物を用いて確認することができる。例えば、腎臓中の２０－ＨＥＴＥ産生量の抑制や、多発性嚢胞腎の改善を確認することによってできる。
Moreover, the effectiveness of the compound of the present invention can be confirmed using a model animal such as a mouse or a rat. For example, it can be confirmed by suppressing the amount of 20-HETE produced in the kidney and confirming the improvement of polycystic kidney disease.
本発明により、３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸は、優れた２０－ＨＥＴＥを産生する酵素を阻害する作用を有することが示された。従って、本発明化合物は、多発性嚢胞腎に由来する疾病等の予防又は治療に有効な医薬品を提供することが可能となり、患者の負担を軽減し、医薬品産業の発達に寄与することが期待される。また、本発明の３－［８－［６－（１，２，４－トリアゾル－１－イル）ピリジン－３－イル］オキシオクチル］オキセタン－３－カルボン酸の結晶は、優れた保存安定性、その他の物性を有しており、医薬品原体として有用である。 According to the present invention, 3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid produces excellent 20-HETE. It has been shown to have an action of inhibiting the enzyme. Therefore, the compound of the present invention is expected to be able to provide a drug effective for the prevention or treatment of diseases derived from polycystic kidney disease, reduce the burden on patients, and contribute to the development of the pharmaceutical industry. To. Further, the crystals of 3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid of the present invention have excellent storage stability. It has other physical properties and is useful as a drug substance.
Claims (2)
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝４．７度、１４．１度、１７．５度、及び１８．９度にピークを有する；並びに
（ｂ）示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）において、吸熱ピークが１２１℃～１２５℃にある。 Of 3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid having the following physical characteristics (a) to (b) crystal.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.7 degrees, 14.1 degrees, 17.5 degrees, and 18.9 degrees; and (b) differential thermal analysis / heat. In mass measurement (TG / DTA), the endothermic peak is at 121 ° C to 125 ° C.
溶媒群Ａは、
酢酸エチル及びｎ－ヘキサンの混合液、酢酸エチル、ＭＴＢＥ、トルエン、ＴＨＦ、メタノール、エタノール、２－プロパノール、アセトン、アセトニトリル、並びにＤＭＦ
からなる群である、前記の製造方法。
（ａ）粉末Ｘ線回折（Ｃｕ－Ｋα）において、２θ＝４．７度、１４．１度、１７．５度、及び１８．９度にピークを有する；並びに
（ｂ）示差熱分析／熱質量測定（ＴＧ／ＤＴＡ）において、吸熱ピークが１２１℃～１２５℃にある。 3- [8- [6- (1,2,4-triazol-1-yl) pyridin-3-yl] oxyoctyl] oxetane-3-carboxylic acid is added with one solvent selected from the following solvent group A. A method for producing crystals having the following physical properties (a) to (b), which comprises preparing a solution, crystallization, and drying the obtained crystals.
Solvent group A
A mixture of ethyl acetate and n-hexane, ethyl acetate, MTBE, toluene, THF, methanol, ethanol, 2-propanol, acetone, acetonitrile, and DMF.
The above-mentioned manufacturing method, which is a group consisting of.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.7 degrees, 14.1 degrees, 17.5 degrees, and 18.9 degrees; and (b) differential thermal analysis / heat. In mass measurement (TG / DTA), the endothermic peak is at 121 ° C to 125 ° C.
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| JP2022029880A true JP2022029880A (en) | 2022-02-18 |
Family
ID=80323767
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| Country | Link |
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2020
- 2020-08-06 JP JP2020133450A patent/JP2022029880A/en active Pending
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