JPWO2012115209A1 - Soluble epoxide hydrolase inhibitor - Google Patents
Soluble epoxide hydrolase inhibitor Download PDFInfo
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- JPWO2012115209A1 JPWO2012115209A1 JP2013501127A JP2013501127A JPWO2012115209A1 JP WO2012115209 A1 JPWO2012115209 A1 JP WO2012115209A1 JP 2013501127 A JP2013501127 A JP 2013501127A JP 2013501127 A JP2013501127 A JP 2013501127A JP WO2012115209 A1 JPWO2012115209 A1 JP WO2012115209A1
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Abstract
本発明は、下記一般式(I)で表される化合物を含む可溶性エポキシドハイドロラーゼ阻害剤を提供する。一般式(I)中、Rは水素原子、α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基、複素環基、炭素数2〜8のアルキル基、又はアリール基を示す。Lは炭素数4〜10の脂肪族炭化水素基を示し、Xはヒドロキシ基又はカルボキシ基を示す。nは0〜2の整数を示すThe present invention provides a soluble epoxide hydrolase inhibitor comprising a compound represented by the following general formula (I). In general formula (I), R represents a hydrogen atom, an α-amino acid or a residue obtained by removing one amino group from an amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group. L represents an aliphatic hydrocarbon group having 4 to 10 carbon atoms, and X represents a hydroxy group or a carboxy group. n represents an integer of 0 to 2
Description
本発明は、可溶性エポキシドハイドロラーゼ阻害剤に関する。 The present invention relates to a soluble epoxide hydrolase inhibitor.
アラキドン酸カスケードは、様々な細胞外及び/又は細胞内シグナルに応答してアラキドン酸が原形質膜の脂質貯蔵から遊離される脂質シグナル伝達カスケードであり、生体内の広範に分布する。遊離されたアラキドン酸は、様々な酸化酵素によって、炎症において重要な役割をするシグナル伝達脂質に転換される。これらの脂質シグナル伝達カスケードを制御することは、多数の炎症性障害を処置するために使用される多くの市販薬にとって依然として重要な戦略である。例えば、非ステロイド系抗炎症薬(NSAID)は、シクロオキシゲナーゼ(COX1及びCOX2)を阻害することによりアラキドン酸のプロスタグランジンへの転換を抑制する。 The arachidonic acid cascade is a lipid signaling cascade in which arachidonic acid is released from the lipid stores of the plasma membrane in response to various extracellular and / or intracellular signals and is widely distributed in vivo. The released arachidonic acid is converted by various oxidases into signaling lipids that play an important role in inflammation. Controlling these lipid signaling cascades remains an important strategy for many marketed drugs used to treat a number of inflammatory disorders. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the conversion of arachidonic acid to prostaglandins by inhibiting cyclooxygenases (COX1 and COX2).
ある種のシトクロムP450依存性酵素が、アラキドン酸をエポキシエイコサトリエン酸(EET)として公知である一連のエポキシド誘導体に転換する。これらのEETは、全身に発現が認められ、特に内皮細胞、腎臓、肝臓で高い発現が見られる。アラキドン酸の代謝物であるプロスタグランジン及びロイコトリエン経路の多くの最終生成物とは対照的に、EETは様々な抗炎症及び抗高血圧特性を有し、強力な血管拡張薬及び血管透過性のメディエーターであることが公知である。 Certain cytochrome P450-dependent enzymes convert arachidonic acid into a series of epoxide derivatives known as epoxyeicosatrienoic acid (EET). These EETs are expressed throughout the body, and are particularly highly expressed in endothelial cells, kidneys and liver. In contrast to many end products of the prostaglandin and leukotriene pathways, which are metabolites of arachidonic acid, EET has various anti-inflammatory and anti-hypertensive properties, and is a potent vasodilator and vascular permeability mediator It is known that
EETはインビボ(in vivo)で強力な効果を有する一方、EETのエポキシド構造は、可溶性エポキシドハイドロラーゼ(sEH)によって、活性が低いジヒドロキシエイコサトリエン酸(DHET)の形態に急速に加水分解される。sEHの阻害は、高血圧動物の血圧を低下させ(例えば、Circ Res.,87(11),992−8(2000)、及びJ.Biol.Chem.,275,40504−10(2000)参照)たり、炎症促進性の一酸化窒素(NO)、サイトカイン、及び脂質メディエーターの産生を低下させたり、インビボでリポキシンA4産生を増強することによって炎症消散に寄与したりする(例えば、Proc. Natl. Acad. Sci. USA., 102(28), 9772−7(2005)参照)ことが見いだされている。 While EET has a strong effect in vivo, the epoxide structure of EET is rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to the less active form of dihydroxyeicosatrienoic acid (DHET) . Inhibition of sEH reduces blood pressure in hypertensive animals (see, for example, Circ Res., 87 (11), 992-8 (2000), and J. Biol. Chem., 275, 40504-10 (2000)). , Reduce the production of pro-inflammatory nitric oxide (NO), cytokines, and lipid mediators, or contribute to inflammation resolution by enhancing lipoxin A4 production in vivo (see, eg, Proc. Natl. Acad. Sci. USA., 102 (28), 9772-7 (2005)).
またsEHは、2つの機能を持つ酵素であり、EETをDHETに変換するハイドロラーゼ活性のほか、ホスファターゼ活性を有することが明らかとなっている。ホスファターゼ活性の作用については不明な点が多いが、コレステロール代謝に寄与している可能性が示唆されている(例えば、J.Biol.Chem., 283(52),36592−8(2008)参照)。 Further, sEH is an enzyme having two functions, and has been shown to have phosphatase activity in addition to hydrolase activity that converts EET to DHET. Although there are many unclear points regarding the action of phosphatase activity, it has been suggested that it may contribute to cholesterol metabolism (see, for example, J. Biol. Chem., 283 (52), 36592-8 (2008)). .
上記に関連して様々な低分子化合物が、sEHを阻害し、EETレベルを上昇させることが見いだされている(例えば、Annu.Rev.Pharmcol.Toxicol.,45,311−33(2005)、及び特表2010−521475号公報参照)。このような低分子化合物は代表的に、アダマンチル尿素構造又は置換もしくは無置換のフェニル構造を含んでいる。 Various low molecular weight compounds in connection with the above have been found to inhibit sEH and increase EET levels (eg, Annu. Rev. Pharmcol. Toxicol., 45, 311-33 (2005)). (See Special Table 2010-521475). Such low molecular weight compounds typically contain an adamantyl urea structure or a substituted or unsubstituted phenyl structure.
これまでに発見された各種のsEH阻害剤は、いずれもsEHのハイドロラーゼ活性に対する阻害作用のみが確認されており、sEHのホスファターゼ活性を阻害する化合物の報告は少ない(例えば、Recent Patents on Cardiovascular Drug Discovery,2006,1,67−72)。
本発明は、可溶性エポキシドハイドロラーゼ(sEH)のホスファターゼ活性を阻害可能で、優れた可溶性エポキシドハイドロラーゼ阻害活性を有する可溶性エポキシドハイドロラーゼ阻害剤を提供することを課題とする。Each of the various sEH inhibitors discovered so far has only been confirmed to have an inhibitory effect on the hydrolase activity of sEH, and there are few reports on compounds that inhibit the phosphatase activity of sEH (for example, Regent Patents on Cardiovascular Drug). Discovery, 2006, 1, 67-72).
An object of the present invention is to provide a soluble epoxide hydrolase inhibitor capable of inhibiting the phosphatase activity of soluble epoxide hydrolase (sEH) and having excellent soluble epoxide hydrolase inhibitory activity.
前記課題を解決するための具体的手段は以下の通りであり、本発明は以下の態様を包含する。
本発明の第一の態様は、下記一般式(I)で表される化合物を含む可溶性エポキシドハイドロラーゼ阻害剤である。Specific means for solving the above problems are as follows, and the present invention includes the following aspects.
The first aspect of the present invention is a soluble epoxide hydrolase inhibitor containing a compound represented by the following general formula (I).
式中、Rは水素原子、α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基、複素環基、炭素数2〜8のアルキル基、又はアリール基を示す。Lは炭素数4〜10の脂肪族炭化水素基を示し、Xはヒドロキシ基又はカルボキシ基を示す。nは0〜2の整数を示す。 In the formula, R represents a hydrogen atom, a residue obtained by removing one amino group from an α-amino acid or an amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group. L represents an aliphatic hydrocarbon group having 4 to 10 carbon atoms, and X represents a hydroxy group or a carboxy group. n shows the integer of 0-2.
前記一般式(I)で表される化合物は、下記一般式(II)で表される化合物又は一般式(III)で表される化合物であることが好ましい。 The compound represented by the general formula (I) is preferably a compound represented by the following general formula (II) or a compound represented by the general formula (III).
式中、L1、L2及びL3はそれぞれ独立に、炭素数4〜10の脂肪族炭化水素基を示す。X1、X2及びX3はそれぞれ独立に、ヒドロキシ基又はカルボキシ基を示す。n1、n2及びn3はそれぞれ独立に、0〜2の整数を示す。
R1は、水素原子又は下記(A)から(D)のいずれかを示す。
(A)α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基。
(B)フェニル基、炭素数1〜5のアルキル基及びカルバモイル基からなる群より選ばれる少なくとも1種の置換基を有していてもよい含窒素複素環基。
(C)ヒドロキシ基、カルボキシ基、アミノ基、カルバモイルオキシ基、炭素数7〜14のアリールアルキル基、チオウレイド基及びフルオレサミンから水素原子を1つ取り除いて構成される基からなる群より選ばれる少なくとも1種の置換基を有していてもよい炭素数2〜6のアルキル基。
(D)ヒドロキシ基、カルボキシ基、スルホン酸基、カルバモイル基及びアリールカルボニル基からなる群より選ばれる少なくとも1種の置換基を有してもよいアリール基。
R2は、カルボキシ基を有していてもよい炭素数2〜8のアルキレン基、及び硫黄原子からなる群より選ばれる少なくとも1種から構成される2価の連結基を示す。In the formula, L 1 , L 2 and L 3 each independently represent an aliphatic hydrocarbon group having 4 to 10 carbon atoms. X 1 , X 2 and X 3 each independently represent a hydroxy group or a carboxy group. n1, n2, and n3 each independently represents an integer of 0-2.
R 1 represents a hydrogen atom or any of the following (A) to (D).
(A) A residue obtained by removing one amino group from an α-amino acid or amino sugar.
(B) A nitrogen-containing heterocyclic group which may have at least one substituent selected from the group consisting of a phenyl group, an alkyl group having 1 to 5 carbon atoms, and a carbamoyl group.
(C) At least one selected from the group consisting of a hydroxy group, a carboxy group, an amino group, a carbamoyloxy group, an arylalkyl group having 7 to 14 carbon atoms, a thioureido group, and a group formed by removing one hydrogen atom from fluorescamine. The C2-C6 alkyl group which may have a substituent of a seed | species.
(D) An aryl group that may have at least one substituent selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group.
R 2 represents a divalent linking group composed of at least one selected from the group consisting of an alkylene group having 2 to 8 carbon atoms which may have a carboxy group and a sulfur atom.
前記α−アミノ酸は、天然アミノ酸、天然アミノ酸のD体、又は、ヒドロキシ基、カルボキシ基及び炭素数1〜5のアルキル基からなる群より選ばれる少なくとも1種の置換基を有してもよいフェニルグリシンであることが好ましい。 The α-amino acid may have at least one substituent selected from the group consisting of a natural amino acid, a D-form of a natural amino acid, or a hydroxy group, a carboxy group, and an alkyl group having 1 to 5 carbon atoms. Glycine is preferred.
本発明の第二の態様は、下記一般式(IV)で表される化合物である。 The second aspect of the present invention is a compound represented by the following general formula (IV).
式中、R4は水素原子、α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基、複素環基、炭素数2〜8のアルキル基、又はアリール基を示す。Yは下記化学式(Y1)〜(Y4)のいずれかを示す。下記化学式中、*は結合位置を示す。In the formula, R 4 represents a hydrogen atom, a residue obtained by removing one amino group from an α-amino acid or an amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group. Y represents any one of the following chemical formulas (Y1) to (Y4). In the following chemical formula, * indicates a bonding position.
前記一般式(IV)におけるR4は、水素原子であることが好ましい。R 4 in the general formula (IV) is preferably a hydrogen atom.
本発明の第三の態様は、前記可溶性エポキシドハイドロラーゼ阻害剤を含む炎症性疾患の治療剤である。 The third aspect of the present invention is a therapeutic agent for inflammatory diseases comprising the soluble epoxide hydrolase inhibitor.
本発明の第四の態様は、前記可溶性エポキシドハイドロラーゼ阻害剤を含むがん悪液質の治療剤である。 A fourth aspect of the present invention is a cancer cachexia therapeutic agent comprising the soluble epoxide hydrolase inhibitor.
本発明の第五の態様は、前記可溶性エポキシドハイドロラーゼ阻害剤をがん悪液質の治療を必要とする哺乳類に投与することを含むがん悪液質の治療方法である。 A fifth aspect of the present invention is a method for treating cancer cachexia, comprising administering the soluble epoxide hydrolase inhibitor to a mammal in need of treatment for cancer cachexia.
本発明の第六の態様は、前記可溶性エポキシドハイドロラーゼ阻害剤のがん悪液質治療剤への使用である。 The sixth aspect of the present invention is the use of the soluble epoxide hydrolase inhibitor as a therapeutic agent for cancer cachexia.
本発明によれば、可溶性エポキシドハイドロラーゼのホスファターゼ活性を阻害可能で、優れた可溶性エポキシドハイドロラーゼ阻害活性を有する可溶性エポキシドハイドロラーゼ阻害剤を提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, the soluble epoxide hydrolase inhibitor which can inhibit the phosphatase activity of soluble epoxide hydrolase and has the outstanding soluble epoxide hydrolase inhibitory activity can be provided.
本発明の可溶性エポキシドハイドロラーゼ阻害剤は、下記一般式(I)で表される化合物の少なくとも1種を含む。下記一般式(I)で表される特定の構造を有することで、優れた可溶性エポキシドハイドロラーゼ阻害活性(以下、「sEH」ともいう)を示す。さらに可溶性エポキシドハイドロラーゼのホスファターゼ活性を阻害可能である。 The soluble epoxide hydrolase inhibitor of the present invention contains at least one compound represented by the following general formula (I). By having a specific structure represented by the following general formula (I), excellent soluble epoxide hydrolase inhibitory activity (hereinafter also referred to as “sEH”) is exhibited. Furthermore, the phosphatase activity of soluble epoxide hydrolase can be inhibited.
下記一般式(I)で表される化合物は、その構造中に1個又は複数個の不斉炭素原子又は不斉中心を含む場合があり、2種以上の光学異性体が存在する場合もある。本発明は各々の光学異性体及びそれらが任意の割合で含まれる混合物をも全て包含するものである。
また下記一般式(I)で表される化合物は、その構造中に、炭素−炭素二重結合に由来する2種以上の幾何異性体が存在する場合もある。本発明は各々の幾何異性体が任意の割合で含まれる混合物をも全て包含する。The compound represented by the following general formula (I) may contain one or more asymmetric carbon atoms or asymmetric centers in its structure, and may have two or more optical isomers. . The present invention includes all the optical isomers and mixtures containing them in an arbitrary ratio.
Moreover, the compound represented by the following general formula (I) may have two or more geometric isomers derived from a carbon-carbon double bond in the structure. The present invention encompasses all mixtures in which each geometric isomer is contained in an arbitrary ratio.
式中、Rは水素原子、α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基、置換基を有していてもよい複素環基、置換基を有していてもよい炭素数2〜8のアルキル基、又は置換基を有していてもよいアリール基を示す。
Lは炭素数4〜10の脂肪族炭化水素基を示す。XはLで示される脂肪族炭化水素基における置換基であり、ヒドロキシ基又はカルボキシ基を示す。nはLにおける置換基Xの置換数であり、0〜2の整数を示す。In the formula, R is a hydrogen atom, a residue obtained by removing one amino group from an α-amino acid or an amino sugar, a heterocyclic group which may have a substituent, or a carbon number which may have a substituent 2 The alkyl group of -8, or the aryl group which may have a substituent is shown.
L represents an aliphatic hydrocarbon group having 4 to 10 carbon atoms. X is a substituent in the aliphatic hydrocarbon group represented by L, and represents a hydroxy group or a carboxy group. n is the number of substituents X in L and represents an integer of 0 to 2.
一般式(I)のRにおけるα−アミノ酸は特に制限されず、天然アミノ酸であっても、非天然アミノ酸であってもよい。また天然アミノ酸に置換基が導入されたアミノ酸誘導体であってもよい。さらにα−アミノ酸が2以上のアミノ基を有する場合、いずれのアミノ基が取り除かれてもよい。
中でもα−アミノ酸は、sEH阻害活性の観点から、天然アミノ酸、天然アミノ酸のD体、又は、ヒドロキシ基、カルボキシ基及び炭素数1〜5のアルキル基からなる群より選ばれる少なくとも1種の置換基を有してもよいフェニルアラニン若しくはフェニルグリシンであることが好ましく、天然アミノ酸、天然アミノ酸のD体、又は、ヒドロキシ基、カルボキシ基及び炭素数1〜5のアルキル基からなる群より選ばれる少なくとも1種の置換基を有してもよいフェニルグリシンであることがより好ましい。The α-amino acid in R of the general formula (I) is not particularly limited, and may be a natural amino acid or a non-natural amino acid. Moreover, the amino acid derivative by which the substituent was introduce | transduced into the natural amino acid may be sufficient. Further, when the α-amino acid has two or more amino groups, any amino group may be removed.
Among them, α-amino acid is at least one substituent selected from the group consisting of a natural amino acid, a D-form of a natural amino acid, or a hydroxy group, a carboxy group, and an alkyl group having 1 to 5 carbon atoms from the viewpoint of sEH inhibitory activity. It is preferably phenylalanine or phenylglycine optionally having at least one selected from the group consisting of natural amino acids, D-forms of natural amino acids, or hydroxy groups, carboxy groups, and alkyl groups having 1 to 5 carbon atoms. It is more preferable that it is phenylglycine which may have a substituent.
天然アミノ酸は、天然に存在し得るアミノ酸であれば特に制限されない。例えば、グリシン、アラニン、スレオニン、バリン、イソロイシン、チロシン、システイン、シスチン、メチオニン、ヒスチジン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、アルギニン、リシン、ヒドロキシリシン、オルニチン、シトルリン、ホモシステイン、3,4−ジヒドロキシフェニルアラニン、ホモシスチン、ジアミノピメリン酸、ジアミノプロピオン酸、セリン、ロイシン、フェニルアラニン、トリプトファン等が挙げられる。 The natural amino acid is not particularly limited as long as it is an amino acid that can exist in nature. For example, glycine, alanine, threonine, valine, isoleucine, tyrosine, cysteine, cystine, methionine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, hydroxylysine, ornithine, citrulline, homocysteine, 3,4-dihydroxy Examples include phenylalanine, homocystin, diaminopimelic acid, diaminopropionic acid, serine, leucine, phenylalanine, and tryptophan.
天然アミノ酸に置換基が導入されたアミノ酸誘導体における置換基としては、例えば、ニトロ基、ヒドロキシ基、炭素数7〜16のアリールアルキル基、ウレイド基、チオウレイド基、カルボキシ基、フルオレサミンから水素原子を1つ取り除いて構成される基等が挙げられる。前記アミノ酸誘導体における置換基は可能な場合にはさらに置換基を有していてもよい。置換基が有する置換基はアミノ酸誘導体における置換基と同様である。 Examples of the substituent in the amino acid derivative in which a substituent is introduced into a natural amino acid include 1 hydrogen atom from nitro group, hydroxy group, arylalkyl group having 7 to 16 carbon atoms, ureido group, thioureido group, carboxy group, and fluorescamine. Groups and the like constituted by removing one. If possible, the substituent in the amino acid derivative may further have a substituent. The substituent which the substituent has is the same as the substituent in the amino acid derivative.
一般式(I)のRにおけるアミノ糖は、アミノ基を少なくとも1つ有する糖誘導体であれば特に制限されない。具体的には例えば、グルコサミン、ガラクトサミン、マンノサミン、ノイラミン酸等を挙げることができる。 The amino sugar in R of the general formula (I) is not particularly limited as long as it is a sugar derivative having at least one amino group. Specific examples include glucosamine, galactosamine, mannosamine, neuraminic acid and the like.
一般式(I)のRにおける複素環基としては、ヘテロ原子を含む環状基であれば特に制限されず、脂肪族複素環基及び芳香族複素環基のいずれであってもよい。またヘテロ原子としては窒素原子、酸素原子、硫黄原子等を挙げることができる。
中でも、sEH阻害活性の観点から、ヘテロ原子として窒素原子を含む含窒素複素環基であることが好ましく、プリン、ピリジン、ピリダジン、ピロール、イミダゾール、ピラゾール、及びピラゾロンからなる群より選ばれる複素環化合物から水素原子を一つ取り除いて構成される複素環基であることがより好ましく、プリン、ピリジン、及びピラゾロンからなる群より選ばれる複素環化合物から水素原子を一つ取り除いて構成される複素環基であることがさらに好ましい。なお、複素環化合物から水素原子を取り除く位置は特に制限されない。中でも複素環化合物の炭素原子上から取り除かれることが好ましい。The heterocyclic group in R of the general formula (I) is not particularly limited as long as it is a cyclic group containing a hetero atom, and may be either an aliphatic heterocyclic group or an aromatic heterocyclic group. Further, examples of the hetero atom include a nitrogen atom, an oxygen atom, and a sulfur atom.
Among these, from the viewpoint of sEH inhibitory activity, a nitrogen-containing heterocyclic group containing a nitrogen atom as a hetero atom is preferable, and a heterocyclic compound selected from the group consisting of purine, pyridine, pyridazine, pyrrole, imidazole, pyrazole, and pyrazolone More preferably, it is a heterocyclic group constituted by removing one hydrogen atom from the heterocyclic group constituted by removing one hydrogen atom from a heterocyclic compound selected from the group consisting of purine, pyridine and pyrazolone. More preferably. Note that the position at which the hydrogen atom is removed from the heterocyclic compound is not particularly limited. Among these, it is preferable to remove from the carbon atom of the heterocyclic compound.
Rにおける複素環基は置換基を有していてもよい。複素環基における置換基としては、例えば、炭素数1〜5のアルキル基、炭素数14以下のアリール基、カルボキシ基、カルバモイル基、スルホン酸基等を挙げることができる。中でもフェニル基及びカルバモイル基から選ばれる少なくとも1種であることが好ましい。
複素環基における置換基の数は特に制限されないが、3以下であることが好ましい。The heterocyclic group in R may have a substituent. Examples of the substituent in the heterocyclic group include an alkyl group having 1 to 5 carbon atoms, an aryl group having 14 or less carbon atoms, a carboxy group, a carbamoyl group, and a sulfonic acid group. Among these, at least one selected from a phenyl group and a carbamoyl group is preferable.
The number of substituents in the heterocyclic group is not particularly limited, but is preferably 3 or less.
一般式(I)のRにおける炭素数2〜8のアルキル基としては、直鎖状、分岐鎖状及び環状のいずれであってもよい。なかでも直鎖状又は分岐鎖状であることが好ましく、直鎖状であることがより好ましい。また炭素数は2〜6であることが好ましい。なお、アルキル基の炭素数にはアルキル基上の置換基の炭素数は含まれない。 The alkyl group having 2 to 8 carbon atoms in R of the general formula (I) may be linear, branched or cyclic. Especially, it is preferable that it is linear or branched, and it is more preferable that it is linear. Moreover, it is preferable that carbon number is 2-6. The carbon number of the alkyl group does not include the carbon number of the substituent on the alkyl group.
Rにおけるアルキル基は置換基を有していてもよい。アルキル基における置換基としては、炭素数1〜5のアルキル基、炭素数14以下のアリール基、炭素数16以下のアリールアルキル基、ヒドロキシ基、カルボキシ基、カルバモイル基、スルホン酸基、アミノ基、カルバモイルオキシ基、ウレイド基、チオウレイド基、アルキルスルフィド基、アルキルジスルフィド基、一般式(I)で表される化合物からRを取り除いて構成される基、フルオレサミンから水素原子を1つ取り除いて構成される基等を挙げることができる。中でも、ヒドロキシ基、カルボキシ基、アミノ基、カルバモイルオキシ基、炭素数7〜14のアリールアルキル基、チオウレイド基、一般式(I)で表される化合物からRを取り除いて構成される基、及びフルオレサミンから水素原子を1つ取り除いて構成される基からなる群より選ばれる少なくとも1種であることが好ましい。 The alkyl group in R may have a substituent. As the substituent in the alkyl group, an alkyl group having 1 to 5 carbon atoms, an aryl group having 14 or less carbon atoms, an arylalkyl group having 16 or less carbon atoms, a hydroxy group, a carboxy group, a carbamoyl group, a sulfonic acid group, an amino group, Carbamoyloxy group, ureido group, thioureido group, alkyl sulfide group, alkyl disulfide group, a group constituted by removing R from the compound represented by formula (I), and constituted by removing one hydrogen atom from fluorescamine Groups and the like. Among them, a hydroxy group, a carboxy group, an amino group, a carbamoyloxy group, an arylalkyl group having 7 to 14 carbon atoms, a thioureido group, a group constituted by removing R from a compound represented by the general formula (I), and fluorescamine It is preferably at least one selected from the group consisting of groups constituted by removing one hydrogen atom from the group.
アルキル基における置換基の数は特に制限されないが、3以下であることが好ましい。
またアルキル基における置換基は可能な場合にはさらに置換基を有していてもよい。置換基が有する置換基はアルキル基における置換基と同様である。The number of substituents in the alkyl group is not particularly limited, but is preferably 3 or less.
Moreover, the substituent in the alkyl group may further have a substituent if possible. The substituent which the substituent has is the same as the substituent in the alkyl group.
一般式(I)のRにおけるアリール基は、炭素数6〜14のアリール基であることが好ましく、炭素数6〜10のアリール基であることがより好ましく、フェニル基であることがさらに好ましい。 The aryl group in R of the general formula (I) is preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and further preferably a phenyl group.
Rにおけるアリール基は置換基を有していてもよい。アリール基における置換基としては、炭素数1〜5のアルキル基、炭素数14以下のアリール基、ヒドロキシ基、カルボキシ基、スルホン酸基、カルバモイル基、アリールカルボニル基等を挙げることができる。中でも、ヒドロキシ基、カルボキシ基、スルホン酸基、カルバモイル基及びアリールカルボニル基からなる群より選ばれる少なくとも1種であることが好ましい。 The aryl group in R may have a substituent. Examples of the substituent in the aryl group include an alkyl group having 1 to 5 carbon atoms, an aryl group having 14 or less carbon atoms, a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group. Among these, at least one selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group is preferable.
アリール基における置換基の数は特に制限されないが、3以下であることが好ましい。
またアリール基における置換基は可能な場合にはさらに置換基を有していてもよい。置換基が有する置換基はアリール基における置換基と同様である。さらにアリール基における置換基は可能な場合には、置換基同士が結合して環状構造を形成してもよい。The number of substituents in the aryl group is not particularly limited, but is preferably 3 or less.
Moreover, the substituent in the aryl group may further have a substituent, if possible. The substituent which the substituent has is the same as the substituent in the aryl group. Furthermore, when the substituent in the aryl group is possible, the substituents may be bonded to form a cyclic structure.
Lで示される炭素数4〜10の脂肪族炭化水素基は、直鎖状、分岐鎖状及び環状のいずれであってもよい。また不飽和結合を含んでいてもよい。中でも直鎖状又は分岐鎖状の不飽和結合を含んでもよい脂肪族炭化水素基であることが好ましい。 The aliphatic hydrocarbon group having 4 to 10 carbon atoms represented by L may be linear, branched or cyclic. Moreover, the unsaturated bond may be included. Among these, an aliphatic hydrocarbon group that may contain a linear or branched unsaturated bond is preferable.
一般式(I)において、−L−Xnで表される基は、sEH阻害活性の観点から、下記一般式(V)、化学式(Y1)〜(Y4)のいずれかで表されることが好ましい。In formula (I), the group represented by -L-X n, from the viewpoint of sEH inhibitory activity, the following formula (V), formula (Y1) ~ one of represented thing (Y4) preferable.
一般式(V)中、Z1及びZ2はそれぞれ独立して、水素原子若しくはヒドロキシ基であるか、又は一緒になって単結合を形成する。なお、化学式中の「*」は結合位置を示す。In general formula (V), Z 1 and Z 2 are each independently a hydrogen atom or a hydroxy group, or together form a single bond. In the chemical formula, “*” indicates a bonding position.
前記一般式(I)で表される化合物は、下記一般式(II)で表される化合物又は一般式(III)で表される化合物であることが好ましい。 The compound represented by the general formula (I) is preferably a compound represented by the following general formula (II) or a compound represented by the general formula (III).
式中、L1、L2及びL3はそれぞれ独立に、炭素数4〜10の脂肪族炭化水素基を示す。L1、L2及びL3の詳細は、一般式(I)におけるLと同様であり、好ましい態様も同様である。また、−L1−(X1)n1、−L2−(X2)n2及び−L3−(X3)n3で表される基の好ましい態様は、−L−Xnで表される基と同様である。In the formula, L 1 , L 2 and L 3 each independently represent an aliphatic hydrocarbon group having 4 to 10 carbon atoms. The details of L 1 , L 2 and L 3 are the same as L in general formula (I), and the preferred embodiments are also the same. Further, -L 1 - (X 1) n1, -L 2 - (X 2) n2 and -L 3 - preferable embodiment of the group represented by (X 3) n3 is represented by -L-X n Same as the group.
R1は、水素原子又は下記(A)から(D)のいずれかを示す。
(A)α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基。
(B)フェニル基、炭素数1〜5のアルキル基及びカルバモイル基からなる群より選ばれる少なくとも1種の置換基を有していてもよい含窒素複素環基。
(C)ヒドロキシ基、カルボキシ基、アミノ基、カルバモイルオキシ基、炭素数7〜14のアリールアルキル基、チオウレイド基及びフルオレサミンから水素原子を1つ取り除いて構成される基からなる群より選ばれる少なくとも1種の置換基を有していてもよい炭素数2〜6のアルキル基。但し、カルボキシメチル基を有する場合を除く。
(D)ヒドロキシ基、カルボキシ基、スルホン酸基、カルバモイル基及びアリールカルボニル基からなる群より選ばれる少なくとも1種の置換基を有してもよいアリール基。R 1 represents a hydrogen atom or any of the following (A) to (D).
(A) A residue obtained by removing one amino group from an α-amino acid or amino sugar.
(B) A nitrogen-containing heterocyclic group which may have at least one substituent selected from the group consisting of a phenyl group, an alkyl group having 1 to 5 carbon atoms, and a carbamoyl group.
(C) At least one selected from the group consisting of a hydroxy group, a carboxy group, an amino group, a carbamoyloxy group, an arylalkyl group having 7 to 14 carbon atoms, a thioureido group, and a group formed by removing one hydrogen atom from fluorescamine. The C2-C6 alkyl group which may have a substituent of a seed | species. However, the case where it has a carboxymethyl group is excluded.
(D) An aryl group that may have at least one substituent selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group.
R1におけるα−アミノ酸及びアミノ糖は、一般式(I)のRにおけるα−アミノ酸及びアミノ糖と同義であり、好ましい態様も同様である。The α-amino acid and amino sugar in R 1 are synonymous with the α-amino acid and amino sugar in R of the general formula (I), and the preferred embodiments are also the same.
R1における含窒素複素環基は、少なくとも窒素原子を含む環状基であれば特に制限されず、飽和複素環基、不飽和複素環基及び芳香族複素環基のいずれであってもよい。またヘテロ原子として窒素原子に加えて、酸素原子、硫黄原子等を含んでいてもよい。The nitrogen-containing heterocyclic group in R 1 is not particularly limited as long as it is a cyclic group containing at least a nitrogen atom, and may be any of a saturated heterocyclic group, an unsaturated heterocyclic group, and an aromatic heterocyclic group. Moreover, in addition to a nitrogen atom as a hetero atom, an oxygen atom, a sulfur atom, etc. may be included.
含窒素複素環基の具体例としては、プリン、ピリジン、ピリダジン、ピロール、イミダゾール、ピラゾール、ピラゾロンからなる群より選ばれる複素環化合物から水素原子を一つ取り除いて構成される複素環基を挙げることができる。中でも、プリン、ピリジン、及びピラゾロンからなる群より選ばれる複素環化合物から水素原子を一つ取り除いて構成される複素環基であることが好ましい。
R1における含窒素複素環基の具体例を以下に示すが、本発明はこれらに限定されない。なお、以下の化学式中、「*」は結合位置を示す。Specific examples of the nitrogen-containing heterocyclic group include a heterocyclic group constituted by removing one hydrogen atom from a heterocyclic compound selected from the group consisting of purine, pyridine, pyridazine, pyrrole, imidazole, pyrazole, and pyrazolone. Can do. Among these, a heterocyclic group constituted by removing one hydrogen atom from a heterocyclic compound selected from the group consisting of purine, pyridine, and pyrazolone is preferable.
Specific examples of the nitrogen-containing heterocyclic group for R 1 are shown below, but the present invention is not limited thereto. In the chemical formulas below, “*” represents a bonding position.
R1における炭素数2〜6のアルキル基は、ヒドロキシ基、カルボキシ基、アミノ基、カルバモイルオキシ基、炭素数7〜14のアリールアルキル基、チオウレイド基、及びフルオレサミンから水素原子を1つ取り除いて構成される基からなる群より選ばれる少なくとも1種の置換基を有していてもよい。これらの置換基は可能な場合にはさらに置換基を有していてもよい。該置換基としては上記と同様の置換基を挙げることができる。
R1におけるアルキル基の具体例を以下に示すが、本発明はこれらに限定されない。なお、以下の化学式中、「*」は結合位置を示す。The alkyl group having 2 to 6 carbon atoms in R 1 is formed by removing one hydrogen atom from a hydroxy group, a carboxy group, an amino group, a carbamoyloxy group, an arylalkyl group having 7 to 14 carbon atoms, a thioureido group, and fluorescamine. It may have at least one substituent selected from the group consisting of the above groups. These substituents may further have a substituent if possible. Examples of the substituent include the same substituents as described above.
Specific examples of the alkyl group for R 1 are shown below, but the present invention is not limited thereto. In the chemical formulas below, “*” represents a bonding position.
R1におけるアリール基としては、炭素数6〜14以下のアリール基であることが好ましく、炭素数6〜10のアリール基であることがより好ましく、フェニル基であることがさらに好ましい。The aryl group in R 1 is preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and further preferably a phenyl group.
R1におけるアリール基は、ヒドロキシ基、カルボキシ基、スルホン酸基、カルバモイル基及びアリールカルボニル基からなる群より選ばれる少なくとも1種の置換基を有していてもよい。アリール基における置換基の数は特に制限されないが、3以下であることが好ましい。またアリール基における置換基は可能な場合にはさらに置換基を有していてもよい。置換基が有する置換基はアリール基における置換基と同様である。さらにアリール基における置換基は可能な場合には、置換基同士が結合して環状構造を形成してもよい
R1におけるアリール基の具体例を以下に示すが、本発明はこれらに限定されない。なお、以下の化学式中、「*」は結合位置を示す。The aryl group in R 1 may have at least one substituent selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group. The number of substituents in the aryl group is not particularly limited, but is preferably 3 or less. Moreover, the substituent in the aryl group may further have a substituent, if possible. The substituent which the substituent has is the same as the substituent in the aryl group. Furthermore, when the substituent in the aryl group is possible, the substituents may be bonded to each other to form a cyclic structure. Specific examples of the aryl group in R 1 are shown below, but the present invention is not limited thereto. In the chemical formulas below, “*” represents a bonding position.
R2は、カルボキシ基を有していてもよい炭素数2〜8のアルキレン基、及び硫黄原子からなる群より選ばれる少なくとも1種から構成される2価の連結基を示す。
以下にR2で示される2価の連結基の具体例を示すが、本発明はこれらに限定されない。なお、以下の化学式中、「*」は結合位置を示す。R 2 represents a divalent linking group composed of at least one selected from the group consisting of an alkylene group having 2 to 8 carbon atoms which may have a carboxy group and a sulfur atom.
Specific examples of the divalent linking group represented by R 2 are shown below, but the present invention is not limited thereto. In the chemical formulas below, “*” represents a bonding position.
本発明の一般式(I)で表される化合物は、下記一般式(IV)で表される化合物で表されることもまた好ましい。一般式(IV)で表される化合物は一般式(I)における−L−Xnで表される置換基が、特定の構造を有することを特徴とする。これにより、一般式(IV)で表される化合物は、より優れたsEH阻害活性を示すことができる。It is also preferable that the compound represented by the general formula (I) of the present invention is represented by a compound represented by the following general formula (IV). The compound represented by the general formula (IV) is characterized in that the substituent represented by -L- Xn in the general formula (I) has a specific structure. Thereby, the compound represented by general formula (IV) can show the more outstanding sEH inhibitory activity.
一般式(IV)中、R4は水素原子、α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基、複素環基、炭素数2〜8のアルキル基、又はアリール基を示す。Yは下記化学式(Y1)〜(Y4)のいずれかを示す。下記化学式中、*は結合位置を示す。In general formula (IV), R 4 represents a hydrogen atom, a residue obtained by removing one amino group from an α-amino acid or an amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group. Y represents any one of the following chemical formulas (Y1) to (Y4). In the following chemical formula, * indicates a bonding position.
一般式(IV)におけるR4の詳細は、一般式(I)におけるRと同様であり、好ましい態様も同様である。さらにR4は水素原子であることもまた好ましい。Details of R 4 in the general formula (IV) are the same as those in R in the general formula (I), and preferred embodiments are also the same. R 4 is preferably a hydrogen atom.
一般式(I)で表される化合物の具体例を以下に示すが、本発明はこれらに限定されない。なお、表中の「*」はRa、Rb、Rc、Rd、及びReにおける結合位置を示す。Specific examples of the compound represented by formula (I) are shown below, but the present invention is not limited thereto. In the table, “*” represents a bonding position in R a , R b , R c , R d , and R e .
一般式(I)で表される化合物は、化学合成によって得たものでもよく、糸状菌、例えば、スタキボトリス・ミクロスポラ(Stachybotrys microspora、例えば、IFO30018株)の培養物から精製して得たものでもよい。前記一般式(I)で表される化合物を糸状菌の培養物から精製して得る方法として、例えば、スタキボトリス・ミクロスポラの培養液に所定の有機アミノ化合物を添加したときに得られた培養物から目的の化合物を精製することを含む方法が挙げられる。これらの方法は、例えば、特開2004−224737号公報、特開2004−224738号公報、及びWO2007/111203号公報等を適宜参照して行うことができる。 The compound represented by the general formula (I) may be obtained by chemical synthesis or may be obtained by purification from a culture of a filamentous fungus, for example, Stachybotrys microspora (for example, IFO30018 strain). . As a method for obtaining the compound represented by the general formula (I) by purification from a filamentous fungus culture, for example, from a culture obtained when a predetermined organic amino compound is added to a culture solution of Stachybotrys microspora. And a method including purifying the target compound. These methods can be performed by appropriately referring to, for example, JP-A-2004-224737, JP-A-2004-224738, WO2007 / 111203, and the like.
一般式(I)で表される化合物は、鏡像異性体、ジアステレオマー、及び鏡像異性体どうし又はジアステレオマーどうしの混合物でもよい。鏡像異性体、ジアステレオマー、及び鏡像異性体どうし又はジアステレオマーどうしの混合物は、化学合成によって得たものでもよく、糸状菌の培養物から精製して得たものでもよい。糸状菌の培養物から精製して得る場合には、糸状菌の培地に添加する有機アミノ化合物のD体又はL体を用いることで、それぞれに対応した鏡像異性体を得ることができる。 The compound represented by the general formula (I) may be an enantiomer, a diastereomer, and a mixture of enantiomers or diastereomers. Enantiomers, diastereomers, and mixtures of enantiomers or diastereomers may be obtained by chemical synthesis or may be obtained by purification from a filamentous fungal culture. When it is obtained by purification from a filamentous fungus culture, enantiomers corresponding to each can be obtained by using D-form or L-form of an organic amino compound added to the filamentous fungus medium.
また一般式(IV)で表される化合物は、化学合成によって得ることができる。また例えば、下記一般式(I0)で表される化合物(以下、「SMTP誘導体」ともいう)を、糸状菌等から選択される微生物の培養液中に添加して、水酸化反応又は酸化反応させることで製造することもできる。下記一般式(I0)におけるRは、一般式(I)におけるRと同義である。なお、一般式(I0)で表される化合物の製造方法については既述一般式(I)で表される化合物と同様である。Moreover, the compound represented by general formula (IV) can be obtained by chemical synthesis. Further, for example, a compound represented by the following general formula (I 0 ) (hereinafter, also referred to as “SMTP derivative”) is added to a culture solution of a microorganism selected from filamentous fungi and the like, and then hydroxylation reaction or oxidation reaction It can also be manufactured. R in the following general formula (I 0 ) has the same meaning as R in the general formula (I). Note that the manufacturing method of the compound represented by formula (I 0) is the same as the compound represented by the above general formula (I).
一般式(IV)で表される化合物は、鏡像異性体、ジアステレオマー、及び鏡像異性体どうし又はジアステレオマーどうしの混合物でもよい。鏡像異性体、ジアステレオマー、及び鏡像異性体どうし又はジアステレオマーどうしの混合物は、化学合成によって得たものでもよく、糸状菌の培養物から精製して得たものでもよい。糸状菌の培養物から精製して得る場合には、糸状菌の培地に添加する一般式(I0)で表される化合物を適宜選択することで、それぞれに対応した鏡像異性体を得ることができる。The compound represented by the general formula (IV) may be an enantiomer, a diastereomer, and a mixture of enantiomers or diastereomers. Enantiomers, diastereomers, and mixtures of enantiomers or diastereomers may be obtained by chemical synthesis or may be obtained by purification from a filamentous fungal culture. When it is obtained by purification from a filamentous fungus culture, the compound represented by the general formula (I 0 ) to be added to the filamentous fungus medium can be appropriately selected to obtain enantiomers corresponding to each. it can.
一般式(I)で表される化合物は、遊離形態、薬学的に許容され得る塩若しくはエステルの形態、又は溶媒和物の形態で用いることができる。一般式(I)で表される化合物の薬学的に許容され得る塩の形成に好適な無機酸又は有機酸としては、塩酸、臭化水素酸、硫酸、硝酸、リン酸、又はクエン酸、ギ酸、フマール酸、リンゴ酸、酢酸、コハク酸、酒石酸、メタンスルホン酸、p−トルエンスルホン酸等が挙げられる。またナトリウム、カリウム、カルシウム、マグネシウム等のアルカリ金属又はアルカリ土類金属を含む化合物、アミン化合物、又は塩基性アミノ酸も、一般式(I)で表される化合物の薬学的に許容され得る塩の形成に好適である。また、一般式(I)で表される化合物の薬学的に許容され得るエステルの形成には、炭素数1〜10個のアルコール又は炭素数2〜10個のカルボン酸などが好適であり、好ましくは、炭素数1〜4個のアルコール又は炭素数2〜4個のカルボン酸などであり、より好ましくはメチルアルコール、エチルアルコール、酢酸、又はプロピオン酸などである。また、水などが、一般式(I)で表される化合物の薬学的に許容され得る溶媒和物の形成に好適である。 The compound represented by the general formula (I) can be used in a free form, a pharmaceutically acceptable salt or ester form, or a solvate form. Suitable inorganic or organic acids for the formation of pharmaceutically acceptable salts of compounds of general formula (I) include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or citric acid, formic acid , Fumaric acid, malic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Further, a compound containing an alkali metal or alkaline earth metal such as sodium, potassium, calcium, magnesium, an amine compound, or a basic amino acid is also a pharmaceutically acceptable salt of the compound represented by the general formula (I). It is suitable for. In addition, for the formation of a pharmaceutically acceptable ester of the compound represented by the general formula (I), an alcohol having 1 to 10 carbon atoms or a carboxylic acid having 2 to 10 carbon atoms is suitable, preferably Is an alcohol having 1 to 4 carbon atoms or a carboxylic acid having 2 to 4 carbon atoms, and more preferably methyl alcohol, ethyl alcohol, acetic acid, or propionic acid. Water or the like is suitable for forming a pharmaceutically acceptable solvate of the compound represented by the general formula (I).
一般式(I)で表される化合物を含むsEH阻害剤は、種々のsEHを媒介する疾患を処置するために使用することができる。sEHを媒介する疾患としては、例えば、高血圧疾患、心血管疾患、虚血性疾患、高コレステロール疾患、肥満症、自己免疫疾患、炎症性疾患、肺疾患、がん悪液質及び糖尿病関連疾患等を挙げることができる。 An sEH inhibitor comprising a compound represented by general formula (I) can be used to treat various sEH-mediated diseases. Examples of diseases that mediate sEH include hypertensive diseases, cardiovascular diseases, ischemic diseases, high cholesterol diseases, obesity, autoimmune diseases, inflammatory diseases, lung diseases, cancer cachexia, diabetes-related diseases, and the like. Can be mentioned.
一般式(I)で表される化合物を種々の疾患を処置するために医薬組成物として使用する場合、一般式(I)で表される化合物は、遊離形態、薬学的に許容可能な塩又はエステルなど、医薬として通常適用可能な形態で医薬組成物中に含有することができる。
また一般式(I)で表される化合物を含む医薬組成物は、各種投与形態に応じて適宜剤型を変更することができる。経口投与形態としては、錠剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤又はシロップ剤等を挙げることができ、非経口投与形態としては、注射剤、点滴剤、座剤、吸入剤、貼付剤等を挙げることができる。
これらの形態を維持するために、これらの用途に使用可能な周知の溶媒、賦形剤等の添加剤を含むことができる。When the compound represented by the general formula (I) is used as a pharmaceutical composition for treating various diseases, the compound represented by the general formula (I) is a free form, a pharmaceutically acceptable salt or An ester or the like can be contained in a pharmaceutical composition in a form that is usually applicable as a medicine.
Moreover, the pharmaceutical composition containing the compound represented by the general formula (I) can be appropriately changed in dosage form according to various administration forms. Examples of oral dosage forms include tablets, capsules, powders, fine granules, granules, solutions or syrups, and parenteral dosage forms include injections, drops, suppositories, inhalants, A patch etc. can be mentioned.
In order to maintain these forms, additives such as well-known solvents and excipients that can be used in these applications can be included.
一般式(I)で表される化合物を含む医薬組成物は、年齢、体重、症状に応じて適切な投与量で投与することができ、例えば静脈内投与の場合には、成人1日あたり有効成分量として、1mg/kgから25mg/kgの投与、経口投与の場合には、成人1日あたり有効成分量として、2mg/kgから200mg/kgの投与が好ましく、投与期間は、年齢、症状に応じて任意に定めることができる。 The pharmaceutical composition containing the compound represented by the general formula (I) can be administered at an appropriate dose according to the age, body weight, and symptoms. For example, in the case of intravenous administration, it is effective per day for an adult. In the case of administration of 1 mg / kg to 25 mg / kg as an ingredient amount, or oral administration, administration of 2 mg / kg to 200 mg / kg as an active ingredient amount per day for an adult is preferable, and the administration period depends on the age and symptoms. It can be arbitrarily determined depending on the situation.
一般式(I)で表される化合物を含む医薬組成物は、炎症性疾患の治療剤として用いられることが好ましい。すなわち本発明の別の態様は一般式(I)で表される化合物を含む炎症性疾患の治療剤である。一般式(I)で表される化合物を含むことで、炎症反応を効果的に抑制することができ、炎症性疾患を治療することができる。 The pharmaceutical composition containing the compound represented by the general formula (I) is preferably used as a therapeutic agent for inflammatory diseases. That is, another aspect of the present invention is a therapeutic agent for inflammatory diseases comprising a compound represented by the general formula (I). By containing the compound represented by the general formula (I), the inflammatory reaction can be effectively suppressed and inflammatory diseases can be treated.
また一般式(I)で表される化合物を含む医薬組成物は、がん悪液質の治療剤として用いられることが好ましい。すなわち本発明の別の態様は一般式(I)で表される化合物を含むがん悪液質の治療剤である。前記がん悪液質の治療剤は、一般式(I)で表される化合物を含むことで、がん悪液質の特徴的な症状である脂肪や骨格筋の消耗を効果的に抑制することができる。さらにがん悪液質の症状を緩和することでがん化学療法の効果をより向上させることができる。 Moreover, it is preferable that the pharmaceutical composition containing the compound represented by general formula (I) is used as a therapeutic agent for cancer cachexia. That is, another aspect of the present invention is a therapeutic agent for cancer cachexia comprising a compound represented by the general formula (I). The therapeutic agent for cancer cachexia effectively suppresses fat and skeletal muscle wasting that are characteristic symptoms of cancer cachexia by containing the compound represented by the general formula (I). be able to. Furthermore, the effect of cancer chemotherapy can be improved by alleviating the symptoms of cancer cachexia.
さらに一般式(I)で表される化合物は、がん悪液質の治療方法に適用することができる。すなわち本発明の別の態様は一般式(I)で表される化合物を、がん悪液質の治療を必要とする哺乳類に、治療に必要な量で投与することを含むがん悪液質の治療方法である。一般式(I)で表される化合物を、がん悪液質の治療を必要とする哺乳類に投与する方法としては、前記医薬組成物をがん悪液質の治療を必要とする哺乳類に投与する方法が挙げられる。前記医薬組成物の詳細、投与方法等は既述のとおりである。 Furthermore, the compound represented by the general formula (I) can be applied to a method for treating cancer cachexia. That is, another aspect of the present invention relates to cancer cachexia comprising administering a compound represented by the general formula (I) to a mammal in need of treatment for cancer cachexia in an amount necessary for treatment. This is a treatment method. As a method for administering the compound represented by the general formula (I) to a mammal in need of cancer cachexia, the pharmaceutical composition is administered to a mammal in need of cancer cachexia. The method of doing is mentioned. Details of the pharmaceutical composition, administration method and the like are as described above.
以下、本発明を実施例により具体的に説明するが、本発明はこれらの実施例に限定されるものではない。なお、特に断りのない限り「%」は質量基準である。また以下では、一般式(I)で表される化合物をSMTP誘導体ともいう。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. Unless otherwise specified, “%” is based on mass. Hereinafter, the compound represented by the general formula (I) is also referred to as an SMTP derivative.
(SMTP誘導体の調製)
公知の方法(Hasumi et al., J. Antibiot.,60(7); 463−468, 2007)にて培養したSMTP−0を含む培養液を2倍量のメタノールで抽出し、菌体をろ過し、ろ液を回収した。溶媒を留去した後、遠心分離によって上清と沈殿物に分離し、水相に不溶性の沈殿物にアセトンを加えた。これをさらに遠心分離によって分離し、アセトンに溶解する上清を回収、これを濃縮・乾固した。得られた乾燥物をシリカゲルクロマトグラフィーに供し、展開溶媒にヘキサン及びアセトンを用いた。展開溶媒としてヘキサンとアセトンを用いたステップワイズで溶出を行い、ヘキサン:アセトン=60:40のフラクションにSMTP−0を確認した。このフラクションを濃縮・乾固し、得られた粗精製物を添加化合物とした。(Preparation of SMTP derivative)
A culture solution containing SMTP-0 cultured by a known method (Hasumi et al., J. Antibiot., 60 (7); 463-468, 2007) is extracted with twice the amount of methanol, and the cells are filtered. The filtrate was recovered. After the solvent was distilled off, the supernatant and the precipitate were separated by centrifugation, and acetone was added to the precipitate insoluble in the aqueous phase. This was further separated by centrifugation, and the supernatant dissolved in acetone was recovered, and this was concentrated and dried. The obtained dried product was subjected to silica gel chromatography, and hexane and acetone were used as developing solvents. Elution was performed stepwise using hexane and acetone as a developing solvent, and SMTP-0 was confirmed in a fraction of hexane: acetone = 60: 40. This fraction was concentrated and dried, and the resulting crude product was used as an additive compound.
(SMTP誘導体を代謝する糸状菌のスクリーニング)
スクリーニングには、東京農工大学 発酵学研究室が保有する、土壌由来の分離糸状菌131株を使用した。
使用した培地は、3.5(w/v)%グルコース、1(w/v)%コーンスターチ、2(w/v)%大豆ミール、0.5(w/v)%ポリペプトン、0.5(w/v)%細菌用魚エキス、0.3(w/v)%酵母エキス、0.2(w/v)%NaCl、0.05(w/v)%K2HPO4、0.005(w/v)%MgSO4?7H2Oよりなる。培地のpHを5.8に調整した後、0.01(v/v)%となるようCB442を添加し、オートクレーブで滅菌した。
同培地20mLを含む100mL容バッフル付き三角フラスコに、各保存スラントより1白金耳ずつ植菌し、25℃、180rpmで振盪培養した。培養3日目に、フラスコ1本あたり5mLの滅菌水を添加して振盪培養を継続した。
培養4日目に2.5mg/本又は10mg/本となるようアセトンに溶解したSMTP−0を100μL加えさらに培養を継続し、培養7日目に50mLメタノールを加えて1時間振盪抽出した。抽出液の一部を取り分けて、培養上清320μL相当をHPLCで分析し、SMTP−0代謝産物と推定されるピークを多く含む、F039株及びF388を選抜した。(Screening of filamentous fungi that metabolize SMTP derivatives)
For screening, 131 strains of isolated filamentous fungi derived from the fermentology laboratory of Tokyo University of Agriculture and Technology were used.
The medium used was 3.5 (w / v)% glucose, 1 (w / v)% corn starch, 2 (w / v)% soybean meal, 0.5 (w / v)% polypeptone, 0.5 ( w / v)% fish extract for bacteria, 0.3 (w / v)% yeast extract, 0.2 (w / v)% NaCl, 0.05 (w / v)% K 2 HPO 4 , 0.005 (W / v)% MgSO 4 -7H 2 O. After adjusting the pH of the medium to 5.8, CB442 was added to 0.01 (v / v)% and sterilized by autoclaving.
One platinum loop from each storage slant was inoculated into a 100 mL baffle Erlenmeyer flask containing 20 mL of the same medium, and cultured with shaking at 25 ° C. and 180 rpm. On the third day of culture, 5 mL of sterilized water was added per flask, and shaking culture was continued.
On the 4th day of culture, 100 μL of SMTP-0 dissolved in acetone so as to be 2.5 mg / line or 10 mg / line was added, and the culture was further continued. On the 7th day of culture, 50 mL of methanol was added, followed by extraction by shaking for 1 hour. A part of the extract was separated, and 320 μL of the culture supernatant was analyzed by HPLC, and F039 strain and F388 containing many peaks estimated to be SMTP-0 metabolites were selected.
<実施例1>
SMTP−0aの調製
斜面培地からF039を、上記と同様の組成の培地100mLを含む500mL容バッフル付き三角フラスコに植菌し、25℃、180rpmで4日間培養し、これを前培養液とした。同様の培地100mLを含む500mL容バッフル付き三角フラスコに、前培養液を終濃度5%となるよう添加し、同様の条件で培養した。培養3日目に100mg/本となるようアセトンに溶解したSMTP−0を1mL添加して、さらに4日間培養を行った。4日後にメタノールを200mL /フラスコ加えて、2時間振盪抽出した。減圧濾過によって菌体を除去し、上清に含まれるメタノールを留去した。濃縮液を遠心分離し、分離した上清を酢酸エチルで抽出した。得られた酢酸エチル層を濃縮・乾固し、この乾固物と沈殿物をまとめてメタノールに溶かした。前処理及び遠心分離によって、不溶物を除去した後、上清をODSカラム(Inertsil PREP−ODS、30φ×250mm;GL Science)を用いた逆相HPLC(流速25mL/min,カラム温度40℃)で精製した。移動層には(A)0.1%ギ酸水、及び(B)メタノールを用い、(B)溶媒10〜100%の30分間のリニアグラジエントによって溶出し、溶出時間20.6分のピークを分取し、得られたフラクションを濃縮・乾固した。
得られた乾燥物をメタノールに溶解し、再度逆相HPLCを用いて精製した。移動層には(A)0.1%ギ酸水及び(B)アセトニトリルを用い、(B)溶媒50%のアイソクラティック条件にて行い、溶出時間14.2分のピークを分取した。有機溶媒を留去した後、水相を凍結乾燥し、再度、同様の条件でHPLC精製を行った結果、32.3mgの白色粉末を得た。
これを50mM酢酸アンモニウムを含む50%メタノール溶液に溶解し、同様の組成の溶媒を移動層として用い、アイソクラティック条件で逆相HPLCを行った。溶出時間16.2分のピークを分取し、メタノールを留去した。水相を酢酸エチルで抽出し、酢酸エチル層を濃縮・乾固し、19.5mgのSMTP−0aを得た。<Example 1>
Preparation of SMTP-0a F039 from the slant medium was inoculated into a 500 mL baffled Erlenmeyer flask containing 100 mL of medium having the same composition as described above, and cultured at 25 ° C. and 180 rpm for 4 days. A preculture solution was added to a 500 mL baffle Erlenmeyer flask containing 100 mL of the same medium to a final concentration of 5%, and cultured under the same conditions. On the third day of culture, 1 mL of SMTP-0 dissolved in acetone to 100 mg / tube was added, and further cultured for 4 days. Four days later, methanol was added at 200 mL / flask and the mixture was extracted by shaking for 2 hours. The cells were removed by filtration under reduced pressure, and methanol contained in the supernatant was distilled off. The concentrated solution was centrifuged, and the separated supernatant was extracted with ethyl acetate. The obtained ethyl acetate layer was concentrated and dried, and the dried product and the precipitate were combined and dissolved in methanol. After removing insolubles by pretreatment and centrifugation, the supernatant was subjected to reverse phase HPLC (flow rate 25 mL / min, column temperature 40 ° C.) using an ODS column (Inertsil PREP-ODS, 30φ × 250 mm; GL Science). Purified. (A) 0.1% formic acid aqueous solution and (B) methanol are used for the moving bed, and (B) the solvent is eluted with a linear gradient of 10 to 100% for 30 minutes. The obtained fraction was concentrated and dried.
The obtained dried product was dissolved in methanol and purified again using reverse phase HPLC. (A) 0.1% aqueous formic acid and (B) acetonitrile were used for the moving bed, and the reaction was performed under isocratic conditions of (B) 50% solvent, and a peak with an elution time of 14.2 minutes was collected. After distilling off the organic solvent, the aqueous phase was freeze-dried and again subjected to HPLC purification under the same conditions. As a result, 32.3 mg of white powder was obtained.
This was dissolved in a 50% methanol solution containing 50 mM ammonium acetate, and reverse phase HPLC was performed under isocratic conditions using a solvent having the same composition as the moving bed. A peak with an elution time of 16.2 minutes was collected, and methanol was distilled off. The aqueous phase was extracted with ethyl acetate, and the ethyl acetate layer was concentrated and dried to obtain 19.5 mg of SMTP-0a.
<実施例2>
SMTP−0bの調製
斜面培地からF388を、スクリーニングと同様の組成の培地100mLを含む500mL容バッフル付き三角フラスコに植菌し、25℃、180rpmで4日間培養し、これを前培養液とした。同様の培地100mLを含む500mL容バッフル付き三角フラスコに、前培養液を終濃度5%となるよう添加し、同様の条件で培養した。培養2日目に100mg/本となるようアセトンに溶解したSMTP−0を1mL添加して、さらに5日間培養を行った。培養終了日にメタノールを200mL/フラスコ加えて、2時間振盪抽出した。減圧濾過によって菌体を除去し、上清に含まれるメタノールを留去した。濃縮液を遠心分離し、分離した上清を酢酸エチルを用いて分配し、その水層をHP−20カラムに供した。展開溶媒に水とメタノールを用いたステップワイズで溶出を行い、水:メタノール=50:50の画分を濃縮・乾固した。乾固物をメタノールに溶かし、不溶物を除去した後、上清をODSカラム(Inertsil PREP−ODS、30φ×250mm;GL Science)を用いた逆相HPLC(流速25mL/min,カラム温度40℃)で精製した。移動層には(A)0.1%ギ酸水、及び(B)メタノールを用い、(B)溶媒10〜100%の30分間のリニアグラジエントによって溶出し、溶出時間20分のピークを分取し、得られたフラクションを濃縮・乾固した。
得られた乾固物をアセトニトリルと精製水の混合液に溶解し、再度逆相HPLCを用いて精製した。移動層には(A)0.1%ギ酸水及び(B)アセトニトリルを用い、(B)溶媒20%のアイソクラティック条件にて行い、溶出時間22分のピークを分取した。有機溶媒を留去した後、水相を凍結乾燥した。乾固物に対しヘキサン洗浄を3回行った後、乾固させた結果、10.6mgの白色固体としてSMTP−0bを得た。<Example 2>
Preparation of SMTP-0b F388 from the slant medium was inoculated into an Erlenmeyer flask with a 500 mL baffle containing 100 mL of the medium having the same composition as that of the screening, and cultured at 25 ° C. and 180 rpm for 4 days. A preculture solution was added to a 500 mL baffle Erlenmeyer flask containing 100 mL of the same medium to a final concentration of 5%, and cultured under the same conditions. On the second day of culture, 1 mL of SMTP-0 dissolved in acetone was added to a concentration of 100 mg / tube and further cultured for 5 days. Methanol was added at 200 mL / flask at the end of the culture, and the mixture was extracted by shaking for 2 hours. The cells were removed by filtration under reduced pressure, and methanol contained in the supernatant was distilled off. The concentrated solution was centrifuged, the separated supernatant was distributed using ethyl acetate, and the aqueous layer was applied to an HP-20 column. Elution was performed stepwise using water and methanol as the developing solvent, and the water: methanol = 50: 50 fraction was concentrated and dried. The dried product was dissolved in methanol to remove insolubles, and then the supernatant was subjected to reverse phase HPLC (flow rate 25 mL / min, column temperature 40 ° C.) using an ODS column (Inertsil PREP-ODS, 30φ × 250 mm; GL Science). Purified. (A) 0.1% formic acid water and (B) methanol are used for the moving bed, and (B) 10% to 100% solvent is eluted with a 30-minute linear gradient. The obtained fraction was concentrated and dried.
The obtained dried product was dissolved in a mixed solution of acetonitrile and purified water, and purified again using reverse phase HPLC. (A) 0.1% formic acid aqueous solution and (B) acetonitrile were used for the moving layer, and (B) 20% of solvent was used under isocratic conditions, and a peak with an elution time of 22 minutes was collected. After distilling off the organic solvent, the aqueous phase was lyophilized. The dried product was washed with hexane three times and dried to obtain 10.6 mg of white solid as SMTP-0b.
<実施例3>
SMTP−0cの調製
斜面培地からF388を、上記と同様の組成の培地100mLを含む500mL容バッフル付き三角フラスコに植菌し、25℃、180rpmで4日間培養し、これを前培養液とした。同様の培地100mLを含む500mL容バッフル付き三角フラスコに、前培養液を終濃度5%となるよう添加し、同様の条件で培養した。培養2日目に100mg/本となるようアセトンに溶解したSMTP−0を1mL添加して、さらに5日間培養を行った。培養終了日にメタノールを200mL/フラスコ加えて、2時間振盪抽出した。減圧濾過によって菌体を除去し、上清に含まれるメタノールを留去した。濃縮液を遠心分離し、分離した上清を酢酸エチルで抽出した。乾固物をメタノールに溶かし、前処理及び遠心分離によって、不溶物を除去した後、上清をODSカラム(Inertsil PREP−ODS、30φ×250mm;GL Science)を用いた逆相HPLC(流速25mL/min,カラム温度40℃)で精製した。移動層には(A)0.1%ギ酸水、及び(B)メタノールを用い、(B)溶媒50〜100%の30分間のリニアグラジエントによって溶出し、溶出時間26.5分のピークを分取し、得られたフラクションを濃縮・乾固した。
得られた乾固物をアセトニトリルと精製水の混合液に溶解し、再度逆相HPLCを用いて精製した。移動層には(A)0.1%ギ酸水及び(B)アセトニトリルを用い、(B)溶媒30%のアイソクラティック条件にて行い、溶出時間37分のピークを分取した。有機溶媒を留去した後、水相を凍結乾燥した。乾固物に対しヘキサン洗浄を3回行った後、乾固させた結果、8.4mgの薄黄色固体としてSMTP−0cを得た。<Example 3>
Preparation of SMTP-0c F388 was inoculated from the slant medium into a 500 mL baffled Erlenmeyer flask containing 100 mL of medium having the same composition as described above, and cultured at 25 ° C. and 180 rpm for 4 days. A preculture solution was added to a 500 mL baffle Erlenmeyer flask containing 100 mL of the same medium to a final concentration of 5%, and cultured under the same conditions. On the second day of culture, 1 mL of SMTP-0 dissolved in acetone was added to a concentration of 100 mg / tube and further cultured for 5 days. Methanol was added at 200 mL / flask at the end of the culture, and the mixture was extracted by shaking for 2 hours. The cells were removed by filtration under reduced pressure, and methanol contained in the supernatant was distilled off. The concentrated solution was centrifuged, and the separated supernatant was extracted with ethyl acetate. The dried solid was dissolved in methanol, insoluble matters were removed by pretreatment and centrifugation, and then the supernatant was subjected to reverse phase HPLC (flow rate 25 mL / flow rate) using an ODS column (Inertsil PREP-ODS, 30φ × 250 mm; GL Science). min, column temperature 40 ° C.). (A) 0.1% aqueous formic acid and (B) methanol are used for the moving bed, and (B) 50% to 100% solvent is eluted with a 30-minute linear gradient, and a peak with an elution time of 26.5 minutes is obtained. The obtained fraction was concentrated and dried.
The obtained dried product was dissolved in a mixed solution of acetonitrile and purified water, and purified again using reverse phase HPLC. (A) 0.1% formic acid aqueous solution and (B) acetonitrile were used for the moving layer, and (B) the solvent was 30% isocratic, and a peak with an elution time of 37 minutes was collected. After distilling off the organic solvent, the aqueous phase was lyophilized. The dried product was washed three times with hexane and then dried to obtain 8.4 mg of SMTP-0c as a light yellow solid.
<実施例4>
SMTP−0d及びSMTP−0eの調製
SMTP生産菌であるStachybotrys microsporaのスラントからSMTP生産用前培養培地に植菌し、25℃、180rpmで4日間培養した。この培養後の前培養培地を5%(v/v)でSMTP生産用本培養培地100ml×5本に接種し、25℃、180rpmで4日間培養した。本培養4日目に0.1%(w/v)NH4Clを添加し、さらに同条件でNH4Cl添加から8日間培養した。8日目に200mlずつメタノールを加えブロースアウトを行い、2時間、180rpmで撹拌して抽出した。<Example 4>
Preparation of SMTP-0d and SMTP-0e From a slant of Stachybotrys microspora, which is an SMTP producing bacterium, inoculated into a preculture medium for SMTP production, and cultured at 25 ° C. and 180 rpm for 4 days. The preculture medium after this culture was inoculated at 5% (v / v) into 100 ml × 5 main culture medium for SMTP production and cultured at 25 ° C. and 180 rpm for 4 days. On the fourth day of the main culture, 0.1% (w / v) NH 4 Cl was added, and further cultured under the same conditions for 8 days from the addition of NH 4 Cl. On the 8th day, 200 ml of methanol was added and blow-out was performed, followed by extraction with stirring at 180 rpm for 2 hours.
得られたブロース溶液を吸引ろ過により菌体を除去後、メタノールを減圧留去した。残った水層と沈殿物について、溶液に対し等量2回、半量2回で酢酸エチル抽出を行った。酢酸エチル層を合して減圧留去し、オイルポンプで1晩減圧して、乾固させた。乾固物をメタノールに溶かしてプレカラム(LiChrolut RP−18−100mg)に通して前処理した後、ODSカラム(Inertsil PREP−ODS、4.6φ×250mm;GL Science)を用いた逆相HPLC(流速25mL/min、カラム温度40℃)で精製した。移動層には(A)0.1%ギ酸水、及び(B)メタノールを用い、(B)溶媒50〜100%の30分間のリニアグラジエントによって溶出し、溶出時間5分のピーク、12分のピーク、20分のピーク及び26分のピークをそれぞれ分取し、得られたフラクションを濃縮・乾固した。 After removing the bacterial cells from the obtained broth solution by suction filtration, methanol was distilled off under reduced pressure. The remaining aqueous layer and precipitate were extracted with ethyl acetate twice in the same amount and twice in the half amount. The ethyl acetate layers were combined and evaporated under reduced pressure, and the pressure was reduced overnight with an oil pump to dryness. The dried product was dissolved in methanol, pretreated by passing through a precolumn (LiChrolt RP-18-100 mg), and then reverse phase HPLC (flow rate) using an ODS column (Inertsil PREP-ODS, 4.6φ × 250 mm; GL Science). 25 mL / min, column temperature 40 ° C.). (A) 0.1% formic acid aqueous solution and (B) methanol are used for the moving bed, and (B) the solvent is eluted with a linear gradient of 50 to 100% for 30 minutes. A peak, a peak at 20 minutes, and a peak at 26 minutes were collected, and the obtained fractions were concentrated and dried.
得られた5分のピークの乾固物を、再度逆相HPLCを用いて精製した。条件はカラム内温度40℃、流速は25ml/minとし、移動層には(A)0.1%ギ酸水及び(B)メタノールを用い、(B)溶媒45%のアイソクラティック条件にて行い、溶出時間31分のピークを分取した。次いで1回目の逆相HPLC分取における溶出時間12分のピークと合わせ、同じ逆相HPLCにてもう一度分取を行った。条件はカラム内温度40℃、流速は25ml/minとし、移動層には(A)0.1%ギ酸水及び(B)アセトニトリルを用い、(B)溶媒25%のアイソクラティック条件にて行い、溶出時間19分のピークを分取した。単離されたフラクションについて乾固して18.8mgの白色の固体として、SMTP−0eを得た。 The resulting 5 min peak dry matter was again purified using reverse phase HPLC. The conditions are a column temperature of 40 ° C., a flow rate of 25 ml / min, (A) 0.1% formic acid water and (B) methanol are used for the moving bed, and (B) the solvent is 45% isocratic. A peak with an elution time of 31 minutes was collected. Subsequently, it was combined with a peak at an elution time of 12 minutes in the first reverse-phase HPLC fractionation, and fractionated once again on the same reverse-phase HPLC. The conditions are a column internal temperature of 40 ° C., a flow rate of 25 ml / min, (A) 0.1% formic acid water and (B) acetonitrile for the moving bed, and (B) 25% solvent isocratic conditions. A peak with an elution time of 19 minutes was collected. The isolated fraction was dried to give SMTP-0e as a 18.8 mg white solid.
1回目の逆相HPLC分取における溶出時間20分のピークについて、同じ逆相HPLCを用いて精製した。条件はカラム内温度40℃、流速は25ml/minとし、移動層には(A)0.1%ギ酸水及び(B)メタノールを用い、(B)溶媒60%のアイソクラティック条件にて行い、溶出時間29分のピークを分取した。単離されたフラクションについて乾固して、23.7mgの白色の固体として、SMTP−0dを得た。 The peak of 20 minutes elution time in the first reverse phase HPLC fractionation was purified using the same reverse phase HPLC. The conditions are a column internal temperature of 40 ° C., a flow rate of 25 ml / min, (A) 0.1% formic acid water and (B) methanol are used for the moving bed, and (B) the solvent is 60% isocratic. The peak with an elution time of 29 minutes was collected. The isolated fractions were dried to give SMTP-0d as 23.7 mg white solid.
SMTP−0a、0b、0c、0d及び0eの物理化学的性状及び構造解析
UVスペクトルは、メタノールを溶媒として用いmodel320spectrometer(日立ハイテク社製)で測定した。
赤外(IR)スペクトルは、JIR−WINSPEC spectrometer(JEOL社製)を用い、SMTP−0a、SMTP−0d及びSMTP−0eはNaCl法、SMTP−0b及びSMTP−0cはKBr法にて測定した。 MALDI−TOF−MASS(MS)スペクトルは、マトリクスとしてα−シアノ−4−ヒドロキシ桂皮酸を用いて、Voyager DE STR spectrometer (Applied Biosystem社製)で測定した。
NMRスペクトルは、メタノール−d4(Acros Organics社製)を用いて、Alpha−600 spectrometer(JEOL社製)で測定した。
旋光度は、メタノールを溶媒として用いmodel DIP−360(JASCO社製)で測定した。Physicochemical properties and structural analysis of SMTP-0a, 0b, 0c, 0d, and 0e UV spectra were measured with a model 320 spectrometer (manufactured by Hitachi High-Tech) using methanol as a solvent.
Infrared (IR) spectra were measured using a JIR-WINSPEC spectrometer (manufactured by JEOL), SMTP-0a, SMTP-0d and SMTP-0e were measured by the NaCl method, and SMTP-0b and SMTP-0c were measured by the KBr method. The MALDI-TOF-MASS (MS) spectrum was measured with a Voyager DE STR spectrometer (manufactured by Applied Biosystem) using α-cyano-4-hydroxycinnamic acid as a matrix.
The NMR spectrum was measured with Alpha-600 spectrometer (manufactured by JEOL) using methanol-d 4 (manufactured by Acros Organics).
The optical rotation was measured with model DIP-360 (manufactured by JASCO) using methanol as a solvent.
物理化学的性状及び構造解析結果を表1〜表4に示す。
尚、各SMTP−0a、0b、0c、0d及び0eの原子の位置番号は、以下に示すようなSMTP−0と一致させて表記した。Tables 1 to 4 show the physicochemical properties and structural analysis results.
Note that the position numbers of the atoms of each SMTP-0a, 0b, 0c, 0d, and 0e are expressed in accordance with SMTP-0 as shown below.
NMRとMSのデータから、SMTP−0aは21−23番目の炭素原子がなく、代わりに20番目の炭素原子にヒドロキシ基がある構造であった。
UVスペクトルは、213nm,254nm,303nmで極大吸収を認めた。
またIRスペクトルでは、3265cm−1,2933cm−1,1670cm−1,1614cm−1,1464cm−1,1360cm−1,1227cm−1,1161cm−1,1078cm−1に吸収が認められた。From the NMR and MS data, SMTP-0a has a structure having no 21-23th carbon atom and having a hydroxy group at the 20th carbon atom instead.
In the UV spectrum, maximum absorption was observed at 213 nm, 254 nm, and 303 nm.
In addition IR spectra, 3265cm -1, 2933cm -1, 1670cm -1, 1614cm -1, 1464cm -1, 1360cm -1, 1227cm -1, 1161cm -1, absorption was observed at 1078cm -1.
SMTP−0bは19−23番目の炭素原子がなく、代わりに18番目の炭素原子がカルボン酸のカルボニル炭素に変わっている構造であった。
UVスペクトルは、214nm、255nm、303nmで極大吸収を認めた。
またIRスペクトルでは、3290cm−1、2945cm−1、1678cm−1、1610cm−1、1464cm−1、1367cm−1、1209cm−1、1161cm−1、1076cm−1に吸収が認められた。SMTP-0b had a structure in which the 19th to 23rd carbon atoms were not present, and instead the 18th carbon atom was changed to the carbonyl carbon of the carboxylic acid.
In the UV spectrum, maximum absorption was observed at 214 nm, 255 nm, and 303 nm.
In addition IR spectra, 3290cm -1, 2945cm -1, 1678cm -1, 1610cm -1, 1464cm -1, 1367cm -1, 1209cm -1, 1161cm -1, absorption was observed at 1076cm -1.
SMTP−0cは22番目の炭素原子がカルボン酸のカルボニル炭素に変わっている構造であった。
UVスペクトルは、214nm、253nm、302nmで極大吸収を認めた。
またIRスペクトルでは、3277cm−1、2983cm−1、2927cm−1、1689cm−1、1614cm−1、1543cm−1、1466cm−1、1358cm−1、1267cm−1、1167cm−1、1084cm−1に吸収が認められた。SMTP-0c had a structure in which the 22nd carbon atom was changed to the carbonyl carbon of carboxylic acid.
In the UV spectrum, maximum absorption was observed at 214 nm, 253 nm, and 302 nm.
In addition the IR spectrum, absorption at 3277cm -1, 2983cm -1, 2927cm -1 , 1689cm -1, 1614cm -1, 1543cm -1, 1466cm -1, 1358cm -1, 1267cm -1, 1167cm -1, 1084cm -1 Was recognized.
SMTP−0dは24番目の炭素原子にヒドロキシ基を有する構造であった。
UVスペクトルは、213nm、254nm、302nmで極大吸収を認めた。
またIRスペクトルでは、3284cm−1、2966cm−1、2921cm−1、2862cm−1、1670cm−1、1614cm−1、1462cm−1、1360cm−1、1227cm−1、1165cm−1、1078cm−1、1034cm−1に吸収が認められた。SMTP-0d had a structure having a hydroxy group at the 24th carbon atom.
In the UV spectrum, maximum absorption was observed at 213 nm, 254 nm, and 302 nm.
In addition the IR spectrum, 3284cm -1, 2966cm -1, 2921cm -1, 2862cm -1, 1670cm -1, 1614cm -1, 1462cm -1, 1360cm -1, 1227cm -1, 1165cm -1, 1078cm -1, 1034cm Absorption was observed at -1 .
SMTP−0eは20番目と21番目の炭素原子にともにヒドロキシ基がある構造であった。
UVスペクトルは、213nm、255nm、302nmで極大吸収を認めた。
またIRスペクトルでは、3329cm−1、2976cm−1、2937cm−1、2866cm−1、1672cm−1、1608cm−1、1464cm−1、1360cm−1、1221cm−1、1159cm−1、1078cm−1に吸収が認められた。SMTP-0e has a structure in which both the 20th and 21st carbon atoms have a hydroxy group.
In the UV spectrum, maximum absorption was observed at 213 nm, 255 nm, and 302 nm.
In addition the IR spectrum, absorption at 3329cm -1, 2976cm -1, 2937cm -1 , 2866cm -1, 1672cm -1, 1608cm -1, 1464cm -1, 1360cm -1, 1221cm -1, 1159cm -1, 1078cm -1 Was recognized.
<sEH阻害活性の評価1>
−ハイドロラーゼ活性1−
sEH阻害活性の評価は、25mM bis−tris−HCl(pH7.0)100μL/well中、96穴蛍光測定用黒色プレートを用いて行った。
所定の各濃度のSMTP誘導体及びrhsEH(組換えヒトsEH、Cayman Chemical社製)を20nMとなるよう50μLの緩衝液に調製し、10分間室温でインキュベーションした。
インキュベーション後、25μMのsEH基質(3−phenyl−oxirany)−acetic acid cyano−(6−methoxy−naphthalen−2−yl)−methyl ester(PHOME,フナコシ社製)を50μL/wellで添加し、37℃で1分おきに15サイクル、連続的に蛍光強度を測定した。蛍光測定には1420 Multilabel Counter ARVOTM MX(PerkinElmer社製)を用いて、励起波長355nm、測定波長460nmで測定した。実験は2連あるいは3連で行った。結果を表5に示す。<Evaluation of sEH inhibitory activity 1>
-Hydrolase activity 1-
Evaluation of sEH inhibitory activity was carried out using a 96-well black plate for fluorescence measurement in 100 μL / well of 25 mM bis-tris-HCl (pH 7.0).
Each predetermined concentration of the SMTP derivative and rhsEH (recombinant human sEH, manufactured by Cayman Chemical) was prepared in 50 μL of a buffer solution to a concentration of 20 nM, and incubated at room temperature for 10 minutes.
After the incubation, 25 μM sEH substrate (3-phenyl-oxylany) -acetic acid cyano- (6-methoxy-naphthalen-2-yl) -methyl ester (PHOME, manufactured by Funakoshi) was added at 50 μL / well. The fluorescence intensity was measured continuously for 15 cycles every minute. For fluorescence measurement, 1420 Multilabel Counter ARVOTM MX (manufactured by PerkinElmer) was used and measured at an excitation wavelength of 355 nm and a measurement wavelength of 460 nm. Experiments were performed in duplicate or triplicate. The results are shown in Table 5.
<sEH阻害活性の評価2>
−ハイドロラーゼ活性2−
ハイドロラーゼ活性をrhsEHの代わりに精製マウスsEHを用いて評価した。なお、精製マウスsEHは、HitrapTM NHS−activated HP (GE Healthcare, UK)にSMTP−50を結合させたアフィニティーカラムにマウス肝臓ホモジネートをアプライし、12−(3−adamantan−1−yl−ureido)−dodecanoic acidにより溶出後、透析により精製したものを用いた。<Evaluation 2 of sEH inhibitory activity>
-Hydrolase activity 2-
Hydrolase activity was evaluated using purified mouse sEH instead of rhsEH. Purified mouse sEH was obtained by applying mouse liver homogenate to an affinity column in which SMTP-50 was bound to Hitrap ™ NHS-activated HP (GE Healthcare, UK), and 12- (3-adamantan-1-yl-ureido) -After elution with dodecanoic acid, purified by dialysis was used.
sEH阻害活性の評価は、25mM bis−Tris−HCl(pH7.0)100μL/well中、96穴蛍光測定用黒色プレートを用いて行った。
所定の各濃度のSMTP誘導体及びマウスsEHを20nMとなるよう50μLの緩衝液に調製し、10分間室温でインキュベーションした。
インキュベーション後、25μMのsEH基質(3−phenyl−oxirany)−acetic acid cyano−(6−methoxy−naphthalen−2−yl)−methyl ester(PHOME,フナコシ社製)を50μL/wellで添加し、37℃で1分おきに15サイクル、連続的に蛍光強度を測定した。蛍光測定には1420 Multilabel Counter ARVOTM MX(PerkinElmer社製)を用いて、励起波長355nm、測定波長460nmで測定した。実験は2連あるいは3連で行った。結果を表6に示す。Evaluation of the sEH inhibitory activity was performed using a 96-well black plate for fluorescence measurement in 100 μL / well of 25 mM bis-Tris-HCl (pH 7.0).
Each predetermined concentration of the SMTP derivative and mouse sEH were prepared in 50 μL of buffer solution to 20 nM, and incubated at room temperature for 10 minutes.
After the incubation, 25 μM sEH substrate (3-phenyl-oxylany) -acetic acid cyano- (6-methoxy-naphthalen-2-yl) -methyl ester (PHOME, manufactured by Funakoshi) was added at 50 μL / well. The fluorescence intensity was measured continuously for 15 cycles every minute. For fluorescence measurement, 1420 Multilabel Counter ARVOTM MX (manufactured by PerkinElmer) was used and measured at an excitation wavelength of 355 nm and a measurement wavelength of 460 nm. Experiments were performed in duplicate or triplicate. The results are shown in Table 6.
<sEH阻害活性の評価3>
−ホスファターゼ活性1−
sEH阻害活性の評価は、アッセイ用緩衝液として、25mM bis−tris−HCl(pH7.0)を用い、96穴プレートを用いて行った。
96穴プレートに所定の各濃度となるようにSMTP誘導体を2.5μl添加した。次いで濃度が200nMであるrhsEH(組換えヒトsEH、Cayman Chemical社製)溶液を47.5μl添加した。
基質溶液として、0.2mg/lウシ血清アルブミンと2mM MgCl2を含むアッセイ用緩衝液に、5mMとなるよう調製したp−ニトロフェニルホスフェート溶液を50μl添加した後、直ちに、450nmにおける吸光度を37℃で10分おきに12サイクル測定した。
SMTP誘導体としてSMTP−7を用いて測定したところ、IC50は0.25μMであった。<Evaluation of sEH inhibitory activity 3>
-Phosphatase activity 1-
Evaluation of sEH inhibitory activity was carried out using a 96-well plate using 25 mM bis-tris-HCl (pH 7.0) as an assay buffer.
2.5 μl of an SMTP derivative was added to a 96-well plate so as to obtain a predetermined concentration. Next, 47.5 μl of rhsEH (recombinant human sEH, manufactured by Cayman Chemical) solution having a concentration of 200 nM was added.
As a substrate solution, 50 μl of p-nitrophenyl phosphate solution adjusted to 5 mM was added to an assay buffer containing 0.2 mg / l bovine serum albumin and 2 mM MgCl 2, and the absorbance at 450 nm was immediately changed to 37 ° C. For 12 cycles every 10 minutes.
When measured using SMTP-7 as the SMTP derivative, the IC 50 was 0.25 μM.
<sEH阻害活性の評価4>
−ホスファターゼ活性2−
ホスファターゼ活性をrhsEHの代わりに上記と同様にして調製した精製マウスsEHを用い、基質としてAttophos(登録商標、Promega社製)を用いて評価した。
sEH阻害活性の評価は、アッセイ用緩衝液として、20mM HBSS/Hepes(pH7.4、0.1mg/ml ウシ血清アルブミンと1mM MgCl2を含む)を用い、96穴蛍光測定用黒色プレート(#CLS3370)を用いて行った。
96穴蛍光測定用黒色プレートに所定の各濃度となるようにSMTP誘導体を2μl添加した。次いで濃度が10nMである精製マウスsEH溶液を50μl添加した。
基質溶液として、アッセイ用緩衝液に、10μMとなるよう調製したAttophos溶液を50μl添加した後、直ちに、励起波長485nm及び535nmにおける蛍光強度を37℃で1分おきに15サイクル測定した。測定は3連で行った。結果を表7に示す。<Evaluation of sEH inhibitory activity 4>
-Phosphatase activity 2-
The phosphatase activity was evaluated using purified mouse sEH prepared in the same manner as above instead of rhsEH, and using Attophos (registered trademark, manufactured by Promega) as a substrate.
Evaluation of sEH inhibitory activity was carried out using 20 mM HBSS / Hepes (pH 7.4, containing 0.1 mg / ml bovine serum albumin and 1 mM MgCl 2 ) as an assay buffer, and a 96-well fluorescence black plate (# CLS3370). ).
2 μl of an SMTP derivative was added to a 96-well fluorescence measurement black plate so as to obtain predetermined concentrations. Subsequently, 50 μl of purified mouse sEH solution having a concentration of 10 nM was added.
As a substrate solution, 50 μl of the Attophos solution prepared to 10 μM was added to the assay buffer, and immediately, the fluorescence intensity at excitation wavelengths of 485 nm and 535 nm was measured at 37 ° C. every 15 minutes for 15 cycles. Measurements were performed in triplicate. The results are shown in Table 7.
<sEH阻害活性の評価5>
−ホスファターゼ活性3−
ホスファターゼ活性をrhsEHの代わりに精製マウスsEHを用い、基質としてp−ニトロホスフェート(pNPP)を用いて評価した。
96穴プレートに所定の各濃度となるようにSMTP誘導体を2.5μl添加した。次いで濃度が200nMであるマウスsEH溶液を47.5μl添加した。
基質溶液として、0.2mg/lウシ血清アルブミンと2mM MgCl2を含むアッセイ用緩衝液に、5mMとなるよう調製したp−ニトロフェニルホスフェート溶液を50μl添加した後、直ちに、450nmにおける吸光度を37℃で10分おきに12サイクル測定した。<Evaluation of sEH inhibitory activity 5>
-Phosphatase activity 3-
Phosphatase activity was assessed using purified mouse sEH instead of rhsEH and p-nitrophosphate (pNPP) as substrate.
2.5 μl of an SMTP derivative was added to a 96-well plate so as to obtain a predetermined concentration. Next, 47.5 μl of mouse sEH solution having a concentration of 200 nM was added.
As a substrate solution, 50 μl of p-nitrophenyl phosphate solution adjusted to 5 mM was added to an assay buffer containing 0.2 mg / l bovine serum albumin and 2 mM MgCl 2, and the absorbance at 450 nm was immediately changed to 37 ° C. For 12 cycles every 10 minutes.
<sEH阻害活性の評価6>
SMTP誘導体のsEH阻害活性について、HepG2細胞を用いて以下のようにして評価した。
24穴プレートにHepG2細胞を1×106cells/mlの濃度で500μlずつ播種して、37℃、5%CO2のインキュベーターで一晩培養を行い、HepG2細胞をプレートに接着させた。上清を除去後、予めRPMI−1640培地(FBS10%、100μ/ml:penicillin、100μg/ml streptmycin含有)に目的の濃度に調製したSMTP誘導体を500μlずつ添加した。10分間インキュベートした。
上清を除去後、内部標準物質である14,15DHET−d11(14,15−ジヒドロエイコサトリエン酸−d11標識物、最終濃度200ng/ml)と、14,15EET(14,15−エポキシエイコサトリエン酸、最終濃度0.3μM)とをHBSS緩衝液に溶解したものを添加した。次いで初期濃度と同濃度のSMTP誘導体を添加し、37℃、5%CO2のインキュベーターで1時間インキュベートした。インキュベーション終了後、氷上にプレートを置いた状態で、ピペッティングにより細胞をはがし、培地ごとガラスチューブに移した。すぐに酢酸エチル500μlを添加して、ボルテックスミキサにより懸濁させた。4℃、3500rpm、1分間遠心し、上清を別のガラスチューブに移した。窒素ガス置換した遠心エバポレーターで1〜2時間程度、溶媒を除去した後、残渣にメタノール100μlを加えて再懸濁し、10μlをLC−MS分析に供した。LC−MS分析はShimadzu社製のLCMS−2020を用い、内部標準物質を基準として14,15EETから14,15DHETへの変換量を測定することでSMTP誘導体のsEH阻害活性を評価した。結果を表9に示す。<Evaluation of sEH inhibitory activity 6>
The sEH inhibitory activity of the SMTP derivative was evaluated using HepG2 cells as follows.
HepG2 cells were seeded at a concentration of 1 × 10 6 cells / ml at a concentration of 1 × 10 6 cells / ml in a 24-well plate, and cultured overnight in an incubator at 37 ° C. and 5% CO 2 to attach the HepG2 cells to the plate. After removing the supernatant, 500 μl each of the SMTP derivative prepared to the target concentration was added to RPMI-1640 medium (FBS 10%, 100 μ / ml: containing penicillin, 100 μg / ml streptmycin). Incubated for 10 minutes.
After removing the supernatant, 14,15DHET-d11 (14,15-dihydroeicosatrienoic acid-d11 labeled product, final concentration 200 ng / ml) as an internal standard substance, 14,15EET (14,15-epoxyeicosatri) Enic acid, final concentration 0.3 μM) dissolved in HBSS buffer was added. Next, an SMTP derivative having the same concentration as the initial concentration was added, and incubated for 1 hour in an incubator at 37 ° C. and 5% CO 2 . After completion of the incubation, the cells were peeled off by pipetting while the plate was placed on ice, and the medium was transferred to a glass tube. Immediately, 500 μl of ethyl acetate was added and suspended by a vortex mixer. Centrifugation was performed at 4 ° C., 3500 rpm for 1 minute, and the supernatant was transferred to another glass tube. After removing the solvent with a nitrogen gas-substituted centrifugal evaporator for about 1 to 2 hours, 100 μl of methanol was added to the residue and resuspended, and 10 μl was subjected to LC-MS analysis. LC-MS analysis was performed using Shimadzu LCMS-2020, and the amount of conversion from 14,15 EET to 14,15 DHET was measured based on the internal standard substance to evaluate the sEH inhibitory activity of the SMTP derivative. The results are shown in Table 9.
以上から、一般式(I)で表される化合物であるSMTP誘導体は、優れたsEH阻害活性を示すことが分かる。また、従来知られているsEHのハイドロラーゼ活性阻害活性に加えて、ホスファターゼ活性阻害を示すことが分かる。 From the above, it can be seen that the SMTP derivative, which is a compound represented by the general formula (I), exhibits excellent sEH inhibitory activity. Moreover, it turns out that phosphatase activity inhibition is shown in addition to the conventionally known hydrolase activity inhibition activity of sEH.
<がん悪液質に対する作用1>
SMTP誘導体のがん悪液質に対する作用について、がん細胞を移植したマウスを用いて以下のようにして評価した。一般式(I)で表される化合物であるSMTP誘導体としてはSMTP−7を用いた。<Action 1 against cancer cachexia>
The effect of the SMTP derivative on cancer cachexia was evaluated as follows using a mouse transplanted with cancer cells. SMTP-7 was used as the SMTP derivative which is a compound represented by the general formula (I).
使用動物:BALB/c CrSlc オス 8週齢マウス
群構成:(N)ノーマル、n=4;
(NS)ノーマル−SMTP(SMTP誘導体投与群)、n=4;
(C)コントロール(担がん、SMTP誘導体非投与群)、n=6;
(S)SMTP(担がん、SMTP誘導体投与群)、n=6;
投与量・方法:
群分け後、(N)及び(C)群については生理食塩水を、(NS)及び(S)群についてはSMTP−7 10mg/kgを、いずれも10ml/kg用量で腹腔内に投与した。投与は2日に1回とした。また投与に合わせ、体重、摂餌量、腫瘍径の測定を行った。
がん細胞:Colon26(理研セルバンクより供与)
Colon26は、あらかじめBALB/c CrSlc皮下に移植して、大きさが1000mm3前後になったところで摘出した。得られたがん細胞をPBS中に、細胞濃度が10%(w/v)となるように懸濁させて移植用のがん細胞懸濁液を調製した。Animal used: BALB / c CrSlc male 8-week-old mouse group composition: (N) normal, n = 4;
(NS) Normal-SMTP (SMTP derivative administration group), n = 4;
(C) Control (cancer-bearing, SMTP derivative non-administered group), n = 6;
(S) SMTP (cancer bearing, SMTP derivative administration group), n = 6;
Dosage and method:
After grouping, physiological saline was administered intraperitoneally for groups (N) and (C) and SMTP-7 10 mg / kg for groups (NS) and (S), both at a dose of 10 ml / kg. Administration was once every two days. In accordance with the administration, body weight, food intake, and tumor diameter were measured.
Cancer cells: Colon 26 (provided by RIKEN Cell Bank)
Colon 26 was transplanted into BALB / c CrSlc subcutaneously in advance, and was extracted when the size reached about 1000 mm 3 . The obtained cancer cells were suspended in PBS so that the cell concentration was 10% (w / v) to prepare a cancer cell suspension for transplantation.
[実験スケジュール]
予備飼育を1週間行った後、体重で仮群分けを行った。予め調製した移植用のがん細胞懸濁液を100μl/bodyとなるようにマウス皮下に移植した。移植後14日目に、体重および腫瘍サイズによって4群に分けた。群分け後より2日に1回の割合で生理食塩水またはSMTP−7を腹腔内に投与した。投与開始後14日目に解剖し、筋重量および各種臓器重量を測定した。筋重量は、ヒラメ筋及び脛骨筋について測定を行った。また臓器重量については、心臓、腎臓、脾臓、及び肝臓について測定を行った。[Experiment schedule]
After one week of preliminary breeding, provisional grouping was performed based on body weight. A pre-prepared cancer cell suspension for transplantation was transplanted subcutaneously into mice so as to be 100 μl / body. On the 14th day after transplantation, they were divided into 4 groups according to body weight and tumor size. Saline or SMTP-7 was administered intraperitoneally once every two days after grouping. The animals were dissected 14 days after the start of administration, and the muscle weight and various organ weights were measured. Muscle weight was measured for soleus and tibial muscles. The organ weight was measured for the heart, kidney, spleen, and liver.
また、低アルブミン血症は悪液質の病態の一つであるため、投与開始後14日目に血中アルブミン値の定量を以下のようにして行った。
血中アルブミン値の定量は、和光純薬工業、アルブミンB−テストワコーを用い、添付の方法に準じて行った。すなわち、アルブミン発色試薬1mlに対し、標準ウシ血清又はサンプル血漿を4μl加え、十分に攪拌した後、室温で10分間放置した。その後620nmの波長で吸光度を測定し、標準ウシ血清に対応するスタンダードの値より、サンプル中のアルブミン値を算出した。Since hypoalbuminemia is one of the cachexia conditions, blood albumin levels were quantified as follows on the 14th day after the start of administration.
The blood albumin level was quantified using Wako Pure Chemical Industries, Albumin B-Test Wako, according to the attached method. That is, 4 μl of standard bovine serum or sample plasma was added to 1 ml of albumin coloring reagent, and after sufficiently stirring, it was left at room temperature for 10 minutes. Thereafter, the absorbance was measured at a wavelength of 620 nm, and the albumin value in the sample was calculated from the standard value corresponding to the standard bovine serum.
[評価結果]
体重及び摂餌量については、すべての群について、大きな差異は認められなかった。また腫瘍径について、(C)群と(S)群で大きな差異は認められなかった。
筋重量の評価結果を図1及び図2に示す。図1に示すように、コントロールである(C)群においては、(N)群、及びSMTP−7投与群である(S)群と比べて有意にヒラメ筋重量が減少した。
また心臓、腎臓、及び肝臓については、すべての群について、大きな差異は認められなかった。一方、脾臓については、図3に示すように(N)群及び(NS)群に比べて、(C)群は有意に重量増加していた。また(C)群の方が(S)群よりも重量増加する傾向が見られた。
さらに、SMTP−7は悪液質によるアルブミンの低下を改善する傾向をもたらすことがわかった。[Evaluation results]
There were no significant differences in body weight and food consumption for all groups. In addition, regarding the tumor diameter, there was no significant difference between the (C) group and the (S) group.
The evaluation results of the muscle weight are shown in FIGS. As shown in FIG. 1, in the control (C) group, the soleus muscle weight was significantly reduced as compared to the (N) group and the (S) group that was the SMTP-7 administration group.
Regarding the heart, kidney, and liver, no significant difference was observed in all groups. On the other hand, regarding the spleen, as shown in FIG. 3, the weight of the (C) group was significantly increased compared to the (N) group and the (NS) group. Moreover, the tendency for the (C) group to increase in weight was seen from the (S) group.
Furthermore, it has been found that SMTP-7 tends to improve albumin reduction due to cachexia.
<がん悪液質に対する作用2>
次に一般式(I)で表される化合物であるSMTP誘導体として、SMTP−44Dを用い、SMTP誘導体のがん悪液質に対する作用について以下のようにして評価した。<Action 2 against cancer cachexia>
Next, SMTP-44D was used as an SMTP derivative which is a compound represented by the general formula (I), and the action of the SMTP derivative on cancer cachexia was evaluated as follows.
使用動物:BALB/c CrSlc オス 8週齢マウス
群構成:(N)ノーマル、n=4;
(NS)ノーマル−SMTP(SMTP誘導体投与群)、n=4;
(C)コントロール(担がん、SMTP誘導体非投与群)、n=6;
(S)SMTP(担がん、SMTP誘導体投与群)、n=6;
投与量・方法:
群分け後、(N)及び(C)群については生理食塩水を、(NS)及び(S)群についてはSMTP−44D 10mg/kgを、いずれも10ml/kg用量で腹腔内に投与した。投与は2日に1回とした。また投与に合わせ、体重・摂餌量・腫瘍径の測定を行った。
がん細胞:Colon26(理研セルバンクより供与)
Colon26は、あらかじめRPMI−1640培地に10%FBSを添加した培地で培養した。得られたがん細胞をPBS中に懸濁させて移植用のがん細胞懸濁液を調製した。Animal used: BALB / c CrSlc male 8-week-old mouse group composition: (N) normal, n = 4;
(NS) Normal-SMTP (SMTP derivative administration group), n = 4;
(C) Control (cancer-bearing, SMTP derivative non-administered group), n = 6;
(S) SMTP (cancer bearing, SMTP derivative administration group), n = 6;
Dosage and method:
After grouping, physiological saline was administered intraperitoneally for groups (N) and (C), and SMTP-44D 10 mg / kg for groups (NS) and (S), both at a dose of 10 ml / kg. Administration was once every two days. In addition, body weight, food intake, and tumor diameter were measured in accordance with the administration.
Cancer cells: Colon 26 (provided by RIKEN Cell Bank)
Colon 26 was cultured in a medium in which 10% FBS was added to RPMI-1640 medium in advance. The obtained cancer cells were suspended in PBS to prepare a cancer cell suspension for transplantation.
[実験スケジュール]
予備飼育を6日間行った後、体重で仮群分けを行った。予め調製した移植用のがん細胞懸濁液を1×106cells/100μl/bodyとなるようにマウス左腰部皮下に移植した。移植後14日目に、体重および腫瘍サイズによって4群に分けた。群分け後より2日に1回の割合で生理食塩水またはSMTP−44Dを腹腔内に投与した。投与開始後20日目に解剖し、筋重量および各種臓器重量を測定した。筋重量は、ヒラメ筋及び脛骨筋について測定を行った。また臓器重量については、心臓、腎臓、脾臓、及び肝臓について測定を行った。[Experiment schedule]
After preliminary breeding for 6 days, provisional grouping was performed based on body weight. A cancer cell suspension for transplantation prepared in advance was transplanted subcutaneously into the left lumbar region of the mouse so as to be 1 × 10 6 cells / 100 μl / body. On the 14th day after transplantation, they were divided into 4 groups according to body weight and tumor size. Saline or SMTP-44D was administered intraperitoneally once every two days after grouping. The animals were dissected 20 days after the start of administration, and the muscle weight and various organ weights were measured. Muscle weight was measured for soleus and tibial muscles. The organ weight was measured for the heart, kidney, spleen, and liver.
また投与開始後14日目に血中アルブミン値の定量を以下のようにして行った。
血中アルブミン値の定量は、和光純薬工業、アルブミンB−テストワコーを用い、添付の方法に準じて行った。すなわち、アルブミン発色試薬1mlに対し、標準ウシ血清又はサンプル血漿を4μl加え、十分に攪拌した後、室温で10分間放置した。その後620nmの波長で吸光度を測定し、標準ウシ血清に対応するスタンダードの値より、サンプル中のアルブミン値を算出した。On the 14th day after the start of administration, the blood albumin level was quantified as follows.
The blood albumin level was quantified using Wako Pure Chemical Industries, Albumin B-Test Wako, according to the attached method. That is, 4 μl of standard bovine serum or sample plasma was added to 1 ml of albumin coloring reagent, and after sufficiently stirring, it was left at room temperature for 10 minutes. Thereafter, the absorbance was measured at a wavelength of 620 nm, and the albumin value in the sample was calculated from the standard value corresponding to the standard bovine serum.
[評価結果]
体重及び摂餌量については、すべての群について、大きな差異は認められなかった。また腫瘍径について、(C)群と(S)群で大きな差異は認められなかった。
筋重量の評価結果を図4及び図5に示す。図4及び図5に示すようにコントロールである(C)群においては、(N)群、及びSMTP−44D投与群である(S)群と比べて有意に頸骨重量及びヒラメ筋重量が減少した。
また心臓及び腎臓については、すべての群について、大きな差異は認められなかった。一方、肝臓及び脾臓については、図6及び図7に示すように(N)群及び(NS)群に比べて、(C)群は有意に重量増加していた。また(C)群の方が(S)群よりも重量増加する傾向が見られた。
さらに、図8に示すように、SMTP−44Dは悪液質による低アルブミン血症を有意に改善することがわかった。[Evaluation results]
There were no significant differences in body weight and food consumption for all groups. Further, regarding the tumor diameter, no significant difference was observed between the (C) group and the (S) group.
The results of evaluating the muscle weight are shown in FIGS. As shown in FIGS. 4 and 5, in the control (C) group, the tibia weight and the soleus muscle weight were significantly reduced as compared with the (N) group and the (S) group that was administered with SMTP-44D. .
Regarding the heart and kidney, no significant difference was observed in all groups. On the other hand, as for the liver and spleen, as shown in FIGS. 6 and 7, the weight of the (C) group was significantly increased compared to the (N) group and (NS) group. Moreover, the tendency for the (C) group to increase in weight was seen from the (S) group.
Furthermore, as shown in FIG. 8, SMTP-44D was found to significantly improve hypoalbuminemia due to cachexia.
以上から、一般式(I)で表される化合物を投与することで、がん疾患に伴う骨格筋重量の減少を抑制できることがわかる。すなわち、一般式(I)で表される化合物はがん悪液質の治療に効果的である。 From the above, it can be seen that administration of the compound represented by the general formula (I) can suppress a decrease in skeletal muscle weight associated with cancer diseases. That is, the compound represented by the general formula (I) is effective in treating cancer cachexia.
日本国出願2011−038941号の開示はその全体を本明細書に援用する。
本明細書に記載された全ての文献、特許出願、および技術規格は、個々の文献、特許出願、および技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書に参照により取り込まれる。The disclosure of Japanese application 2011-038941 is incorporated herein in its entirety.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually described to be incorporated by reference, Incorporated herein by reference.
Claims (7)
(式中、Rは、水素原子、α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基、複素環基、炭素数2〜8のアルキル基、又はアリール基を示す。Lは、炭素数4〜10の脂肪族炭化水素基を示し、Xは、ヒドロキシ基又はカルボキシ基を示す。nは、0〜2の整数を示す)A soluble epoxide hydrolase inhibitor comprising a compound represented by the following general formula (I).
(In the formula, R represents a hydrogen atom, a residue obtained by removing one amino group from an α-amino acid or an amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group. L represents carbon. (4) represents an aliphatic hydrocarbon group having a number of 4 to 10, wherein X represents a hydroxy group or a carboxy group, and n represents an integer of 0 to 2)
(式中、L1、L2及びL3はそれぞれ独立に、炭素数4〜10の脂肪族炭化水素基を示す。X1、X2及びX3はそれぞれ独立に、ヒドロキシ基又はカルボキシ基を示す。n1、n2及びn3はそれぞれ独立に、0〜2の整数を示す。
R1は、水素原子又は下記(A)から(D)のいずれかを示す。
(A)α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基。
(B)フェニル基、炭素数1〜5のアルキル基及びカルバモイル基からなる群より選ばれる少なくとも1種の置換基を有していてもよい含窒素複素環基。
(C)ヒドロキシ基、カルボキシ基、アミノ基、カルバモイルオキシ基、炭素数7〜14のアリールアルキル基、チオウレイド基及びフルオレサミンから水素原子を1つ取り除いて構成される基からなる群より選ばれる少なくとも1種の置換基を有していてもよい炭素数2〜6のアルキル基。
(D)ヒドロキシ基、カルボキシ基、スルホン酸基、カルバモイル基及びアリールカルボニル基からなる群より選ばれる少なくとも1種の置換基を有してもよいアリール基。
R2は、カルボキシ基を有していてもよい炭素数2〜8のアルキレン基、及び硫黄原子からなる群より選ばれる少なくとも1種から構成される2価の連結基を示す)The soluble epoxide hydrolase inhibitor according to claim 1, wherein the compound represented by the general formula (I) is a compound represented by the following general formula (II) or a compound represented by the general formula (III). .
(In the formula, L 1 , L 2 and L 3 each independently represent an aliphatic hydrocarbon group having 4 to 10 carbon atoms. X 1 , X 2 and X 3 each independently represent a hydroxy group or a carboxy group. N1, n2 and n3 each independently represents an integer of 0 to 2.
R 1 represents a hydrogen atom or any of the following (A) to (D).
(A) A residue obtained by removing one amino group from an α-amino acid or amino sugar.
(B) A nitrogen-containing heterocyclic group which may have at least one substituent selected from the group consisting of a phenyl group, an alkyl group having 1 to 5 carbon atoms, and a carbamoyl group.
(C) At least one selected from the group consisting of a hydroxy group, a carboxy group, an amino group, a carbamoyloxy group, an arylalkyl group having 7 to 14 carbon atoms, a thioureido group, and a group formed by removing one hydrogen atom from fluorescamine. The C2-C6 alkyl group which may have a substituent of a seed | species.
(D) An aryl group that may have at least one substituent selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group.
R 2 represents a divalent linking group composed of at least one selected from the group consisting of an alkylene group having 2 to 8 carbon atoms which may have a carboxy group and a sulfur atom.
(式中、R4は、水素原子、α−アミノ酸若しくはアミノ糖からアミノ基を1つ取り除いた残基、複素環基、炭素数2〜8のアルキル基、又はアリール基を示す。Yは、下記化学式(Y1)〜(Y4)のいずれかを示す。下記化学式中、*は結合位置を示す)
(In the formula, R 4 represents a hydrogen atom, a residue obtained by removing one amino group from an α-amino acid or an amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group. Y represents One of the following chemical formulas (Y1) to (Y4) is shown (in the following chemical formula, * indicates a bonding position)
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