JP7208624B2 - Novel compounds, agents for the prevention and/or treatment of inflammatory diseases, or carbon monoxide delivery substances - Google Patents
Novel compounds, agents for the prevention and/or treatment of inflammatory diseases, or carbon monoxide delivery substances Download PDFInfo
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- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 title claims description 55
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
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Description
本発明は、新規化合物、その新規化合物を有する炎症性疾患の予防及び／又は治療のための薬剤、又は、その新規化合物を有する一酸化炭素送達物質に関する。 TECHNICAL FIELD The present invention relates to novel compounds, agents for the prevention and/or treatment of inflammatory diseases comprising the novel compounds, or carbon monoxide delivery substances comprising the novel compounds.
一酸化炭素(CO)はヘモグロビン(Hb)の酸素供給を妨げる有毒ガスとして認知されている(非特許文献１)。一方、生体内では微量のCOが常時生産されている。COはヘムが酵素ヘムオキシゲナーゼによって代謝される際にビリベルジンや鉄と共に産生される(非特許文献２)。このような内因性COは生体内でシグナル伝達物質として機能する。微量のCOは抗炎症作用や抗アポトーシス性、抗増殖性等の細胞保護機能を示し、重要な生理学的役割を果たす(非特許文献３)。 Carbon monoxide (CO) is recognized as a toxic gas that prevents hemoglobin (Hb) from supplying oxygen (Non-Patent Document 1). On the other hand, a small amount of CO is constantly produced in vivo. CO is produced together with biliverdin and iron when heme is metabolized by the enzyme heme oxygenase (Non-Patent Document 2). Such endogenous CO functions as a signaling substance in vivo. A trace amount of CO exhibits anti-inflammatory, anti-apoptotic, anti-proliferative, and other cytoprotective functions, and plays an important physiological role (Non-Patent Document 3).
このように一般的に有害ガスとして知られるCOであるが、微量のCOは重要な生理学的役割が報告されており、医学分野で応用するために様々な研究が行われている(非特許文献３)。COは非反応性ガスであるため投与は容易であるが、ガスは投与量の精密制御が困難であり、高濃度のCOを投与すれば酸素欠乏の恐れがある。そのため、酸素欠乏を誘発せずに必要な量のCOを投与できるシステムの開発が望まれている。この問題を解決するためにMotterliniらはCO放出分子であるCORMs (CO releasing molecules)を開発した(非特許文献４)。様々なCORMsの中でも水溶性のCORMsとしてCORM3とCORM401がよく利用されている(図５)。 Although CO is generally known as a harmful gas, trace amounts of CO have been reported to play an important physiological role, and various studies have been conducted to apply it in the medical field (non-patent literature 3). Since CO is a non-reactive gas, it is easy to administer, but it is difficult to precisely control the amount of gas administered, and administration of high-concentration CO may cause oxygen deficiency. Therefore, it is desired to develop a system that can administer the required amount of CO without inducing oxygen deficiency. In order to solve this problem, Motterlini et al. developed CORMs (CO releasing molecules), which are CO releasing molecules (Non-Patent Document 4). Among various CORMs, CORM3 and CORM401 are often used as water-soluble CORMs (Fig. 5).
既存のCORMはCOの生理機能を探索するための研究用試薬として販売されており、よく利用されている。しかしながら、CORMの問題は細胞膜透過性が低いことである。細胞内でのCOによる生理現象を引き起こすためには、一般的に培地中に比較的高濃度(50 μmol/L以上)のCORMを加える投与が必要である。実際に発明者は既存のCORM3及びCORM401を用いて、細胞内へのCOの導入量を調べたところ、CORMの投与量に対してわずか0.2-0.4%のCOが細胞内に存在するのみであった。このような低い効率では、過剰に加えたCORMによるCO以外の生理反応の可能性が除外できず問題がある。また研究用試薬としてのCORMは細胞内へのCOの導入効率が悪く改良の余地がある。 Existing CORMs are marketed as research reagents to explore the physiological functions of CO and are widely used. However, a problem with CORM is its low cell membrane permeability. In order to induce physiological phenomena caused by intracellular CO, it is generally necessary to add CORM to the medium at a relatively high concentration (50 μmol/L or more). When the inventor actually examined the amount of CO introduced into cells using existing CORM3 and CORM401, it was found that only 0.2-0.4% of CO was present in cells relative to the dose of CORM. rice field. With such low efficiency, there is a problem that the possibility of physiological reactions other than CO due to excessive addition of CORM cannot be ruled out. In addition, CORM as a reagent for research has poor CO introduction efficiency into cells, and there is room for improvement.
本発明はかかる問題点に鑑みてなされたものであって、細胞内へCOを効率的に導入できる新規化合物を提供することを目的とする。また、その新規化合物を有する炎症性疾患の予防及び／又は治療のための薬剤を提供することを目的とする。また、その新規化合物を有する一酸化炭素送達物質を提供することを目的とする。 The present invention has been made in view of such problems, and an object of the present invention is to provide a novel compound capable of efficiently introducing CO into cells. Another object of the present invention is to provide a drug for the prevention and/or treatment of inflammatory diseases comprising the novel compound. Another object of the present invention is to provide a carbon monoxide delivery substance containing the novel compound.
本発明にかかる新規化合物は、下記式（Ａ）で示される新規化合物である。ここでＲは水素又は置換基を有してもよい炭素数１～８のアルキル基を示し、置換基としてはハロゲン原子又はアリール基である。 A novel compound according to the present invention is a novel compound represented by the following formula (A). Here, R represents hydrogen or an optionally substituted alkyl group having 1 to 8 carbon atoms, and the substituent is a halogen atom or an aryl group.
本発明にかかる炎症性疾患の予防及び／又は治療のための薬剤は、本発明にかかる新規化合物を有することを特徴とする。 A drug for preventing and/or treating inflammatory diseases according to the present invention is characterized by comprising the novel compound according to the present invention.
本発明にかかる一酸化炭素送達物質は、本発明にかかる新規化合物を有することを特徴とする。 A carbon monoxide delivery substance according to the present invention is characterized by comprising the novel compound according to the present invention.
本発明によれば、細胞内へCOを効率的に導入できる。 According to the present invention, CO can be efficiently introduced into cells.
以下、添付の図面を参照して本発明の実施形態について具体的に説明するが、当該実施形態は本発明の原理の理解を容易にするためのものであり、本発明の範囲は、下記の実施形態に限られるものではなく、当業者が以下の実施形態の構成を適宜置換した他の実施形態も、本発明の範囲に含まれる。 Hereinafter, embodiments of the present invention will be specifically described with reference to the accompanying drawings. The embodiments are intended to facilitate understanding of the principles of the present invention, and the scope of the present invention is as follows. The scope of the present invention is not limited to the embodiments, and other embodiments in which the configurations of the following embodiments are appropriately replaced by those skilled in the art are also included in the scope of the present invention.
本発明者は下記式（Ａ）で示される新規化合物を合成した。ここでＲは水素又は置換基を有してもよい炭素数１～８のアルキル基を示し、置換基としてはハロゲン原子又はアリール基である。 The present inventor synthesized a novel compound represented by the following formula (A). Here, R represents hydrogen or an optionally substituted alkyl group having 1 to 8 carbon atoms, and the substituent is a halogen atom or an aryl group.
アルキル基は、直鎖状であっても、分岐状であってもよい。ただし、Ｒが置換基を有する場合、その炭素数はアルキル基の炭素数に含めないものとする。アルキル基としては、具体的に、メチル基、エチル基、プロピル基（ｎ－プロピル基、イソプロピル基）、ブチル基（ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基）、ペンチル基、ヘキシル基、へプチル基、オクチル基を挙げることができる。置換基としては、ハロゲン原子（塩素原子、臭素原子、フッ素原子等）又はアリール基等を挙げることができる。 Alkyl groups may be straight or branched. However, when R has a substituent, the carbon number thereof shall not be included in the carbon number of the alkyl group. Specific examples of alkyl groups include methyl group, ethyl group, propyl group (n-propyl group, isopropyl group), butyl group (n-butyl group, isobutyl group, sec-butyl group, tert-butyl group), and pentyl. groups, hexyl, heptyl and octyl groups. A halogen atom (a chlorine atom, a bromine atom, a fluorine atom, etc.) or an aryl group etc. can be mentioned as a substituent.
好ましくはＲが水素の場合であり、その場合、本発明にかかる新規化合物は、下記式(Ａ’)で示される。この式(Ａ’)で示される新規化合物はCORM401-Eと称されることがある。 Preferably, R is hydrogen, in which case the novel compounds according to the invention are represented by the following formula (A'). This novel compound represented by formula (A') is sometimes referred to as CORM401-E.
次に本発明にかかる新規化合物の合成方法の一具体例を説明する。式（Ａ）で示される新規化合物は下記に示す１段階の定量的な反応によって合成可能である。 Next, one specific example of the method for synthesizing the novel compound according to the present invention will be described. The novel compound represented by formula (A) can be synthesized by the one-step quantitative reaction shown below.
また式（Ａ’）で示されるCORM401-Eは下記に示すように、市販のCORM401からトリメチルシリルジアゾメタンを用いて温和な条件の１段階の定量的な反応によって合成可能である。このようにCORM401-EはCORM401にメチルエステル基を導入した構造を有する。 CORM401-E represented by formula (A') can be synthesized from commercially available CORM401 by a one-step quantitative reaction under mild conditions using trimethylsilyldiazomethane, as shown below. Thus, CORM401-E has a structure in which a methyl ester group is introduced into CORM401.
本発明にかかる炎症性疾患の予防及び／又は治療のための薬剤は、本発明にかかる上述の新規化合物を有することを特徴とする。COは細胞内で抗炎症作用を示すが、本発明にかかる新規化合物は、既存のCORMで最も高いCO送達効率を示すCORM401と比べて細胞内に約5倍量のCOを送達することができる。したがって本発明にかかる新規化合物は炎症性疾患の予防及び／又は治療のための薬剤として非常に有益である。 A drug for the prevention and/or treatment of inflammatory diseases according to the present invention is characterized by comprising the aforementioned novel compound according to the present invention. CO exhibits an anti-inflammatory effect in cells, and the novel compound according to the present invention can deliver about five times the amount of CO into cells compared to CORM401, which exhibits the highest CO delivery efficiency among existing CORMs. . Therefore, the novel compounds of the present invention are very useful as agents for the prevention and/or treatment of inflammatory diseases.
本明細書において「予防」には疾患の発症を抑えること及び遅延させることが含まれ、疾患になる前の予防だけでなく、治療後の疾患の再発に対する予防も含まれる。一方、「治療」には、症状を治癒すること、症状を改善すること及び症状の進行を抑えることが含まれる。炎症性疾患の予防及び／又は治療のための薬剤の用法用量は適宜変更し得るが、例えば有効成分量として、約0.1～約2000mg/kg/日、好ましくは約1～200mg/kg/日であり、この量を1日1回又は2～3回に分けて投与することができる。 As used herein, "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the onset of disease, but also prevention against recurrence of disease after treatment. On the other hand, "treatment" includes curing symptoms, ameliorating symptoms, and suppressing progression of symptoms. The dosage and administration of drugs for the prevention and/or treatment of inflammatory diseases can be changed as appropriate. This amount can be administered once or divided into 2 to 3 times daily.
本発明の炎症性疾患の予防及び／又は治療のための薬剤の剤型としては、注射剤、舌下剤、経皮パップ剤、錠剤、カプセル剤、細粒剤、シロップ剤、座薬、軟膏剤、点眼剤等が挙げられる。 Dosage forms of the drug for the prevention and/or treatment of inflammatory diseases of the present invention include injections, sublingual agents, transdermal poultices, tablets, capsules, fine granules, syrups, suppositories, ointments, Eye drops etc. are mentioned.
本発明の炎症性疾患の予防及び／又は治療のための薬剤は、剤型に応じて、製剤上許容される賦形剤や増量剤、例えばデキストリン、乳糖、バレイショデンプン、炭酸カルシウム又はアルギン酸ナトリウム等を配剤してもよい。本発明の薬剤の形態は液状、粉体状、カプセル状、顆粒状のいずれでも構わない。注射剤の場合には、溶媒として注射用蒸留水、生理食塩水、リン酸緩衝液、リンゲル液等が使用され、これに分散剤を添加してもよい。 The drug for the prevention and/or treatment of inflammatory diseases of the present invention may contain pharmaceutically acceptable excipients and fillers such as dextrin, lactose, potato starch, calcium carbonate, sodium alginate, etc., depending on the dosage form. may be administered. The form of the drug of the present invention may be liquid, powder, capsule or granule. In the case of injections, distilled water for injection, physiological saline, phosphate buffer, Ringer's solution and the like are used as solvents, to which a dispersant may be added.
本発明の薬剤が適応される患者は、炎症性疾患の患者である。緩解誘導又は緩解維持の目的で本発明の薬剤を投与する。投与経路としては、経口投与、静脈内投与、舌下吸収、経皮吸収、経腸吸収、点眼等が挙げられる。 Patients to whom the drug of the present invention is applied are patients with inflammatory diseases. The agent of the present invention is administered for the purpose of inducing remission or maintaining remission. Examples of administration routes include oral administration, intravenous administration, sublingual absorption, percutaneous absorption, enteral absorption, eye drops and the like.
炎症性疾患として、炎症性腸疾患、慢性関節リウマチ、巨細胞性動脈炎、全身性エリテマトーデス、バージャー病、高安病、古典的結節性多発性動脈炎、川崎病、ウェジナー肉芽腫症、顕微鏡的多発性動脈炎、チャーグ・ストラウス症候群、ヘノッホ・シェーンライン紫斑病、原発性クリオグロブリン血症性血管炎、皮膚白血球破砕性血管炎等が挙げられる。本発明は、これらの疾患の中で、特に炎症性腸疾患に対して好適に適用され得る。炎症性腸疾患は、広義には虚血性大腸炎・小腸炎等も含む腸管の炎症性疾患すべてを指すが、狭義にはクローン病と潰瘍性大腸炎を指す。 Inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, giant cell arteritis, systemic lupus erythematosus, Buerger's disease, Takayasu's disease, classic polyarteritis nodosa, Kawasaki disease, Wegener's granulomatosis, and microscopic multiples Arteritis, Churg-Strauss syndrome, Henoch-Schoenlein purpura, primary cryoglobulinemia vasculitis, cutaneous leukocytoclastic vasculitis and the like. Among these diseases, the present invention can be preferably applied particularly to inflammatory bowel disease. Inflammatory bowel disease broadly refers to all inflammatory diseases of the intestinal tract including ischemic colitis and enteritis, but narrowly refers to Crohn's disease and ulcerative colitis.
本発明にかかる一酸化炭素送達物質は、本発明にかかる上述の新規化合物を有することを特徴とする。上述のように本発明にかかる新規化合物は、既存のCORMで最も高いCO送達効率を示すCORM401と比べて細胞内に約5倍量のCOを送達することができるため、本発明にかかる新規化合物は細胞内CO送達ツール試薬として汎用性が高い。細胞内CO送達ツール試薬として使用する場合は、本発明にかかる一酸化炭素送達物質には、本発明の効果を損なわない範囲にて、本発明の新規化合物以外のその他の成分を配合してもよい。例えば添加物等が挙げられる。 A carbon monoxide delivery substance according to the present invention is characterized by comprising the aforementioned novel compound according to the present invention. As described above, the novel compound according to the present invention can deliver about 5 times more CO into cells than CORM401, which exhibits the highest CO delivery efficiency among existing CORMs. Therefore, the novel compound according to the present invention is highly versatile as an intracellular CO delivery tool reagent. When used as an intracellular CO delivery tool reagent, the carbon monoxide delivery substance according to the present invention may contain other components other than the novel compound of the present invention within a range that does not impair the effects of the present invention. good. Examples include additives.
(1)Tetracarbonyl[N-(dithiocarboxy-κS,κS')-N-methylglycine-methylester]manganite (CORM401-E)の合成
アルゴン雰囲気下、50 mL三口反応容器にメタノール10 mL、ジエチルエーテル5 mL、CORM-401 (0.10 g、0.0003 mol)、10 %TMSジアゾメタン-ヘキサン溶液 (1 mL、0.0006 mol) を加え、室温で3時間撹拌させた。反応終了後、溶媒を減圧留去した。その後、粗生成物を水、ヘキサンで順に洗浄することで橙色の固体を得た。下記に実施例で行ったCORM401-Eの合成ルートを記載する。収率80 %であり収量0.80 gであった。
(1) Synthesis of Tetracarbonyl[N-(dithiocarboxy-κS,κS')-N-methylglycine-methylester]manganite (CORM401-E) Under an argon atmosphere, 10 mL of methanol, 5 mL of diethyl ether, and CORM were added to a 50 mL three-neck reaction vessel. -401 (0.10 g, 0.0003 mol) and 10% TMS diazomethane-hexane solution (1 mL, 0.0006 mol) were added and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. After that, the crude product was washed with water and hexane in order to obtain an orange solid. The synthesis route of CORM401-E performed in Examples is described below. The yield was 80% and the yield was 0.80 g.
なお合成の際に精製する副生成物(CH3)3SiOCH3は沸点が57 ℃と低く、減圧留去することで取り除くことが可能である。 Note that the by-product (CH 3 ) 3 SiOCH 3 refined during the synthesis has a low boiling point of 57° C. and can be removed by distillation under reduced pressure.
CORM-401溶液へTMSCHN2を滴下した直後に気泡の発生が確認された。この気泡は副生成物であるN2であると考えられ、反応が進行していることを確認した。 Bubble generation was confirmed immediately after dropping TMSCHN 2 into the CORM-401 solution. This bubble was considered to be the by-product N2 , confirming the progress of the reaction.
CORM401-Eの1H NMR及びFT-IRスペクトルを図１及び図２に示す。図２に示すFT-IRスペクトル測定の結果、CORM401-EはCORM401と同じ位置にカルボニル基のバンドが観測され、反応の前後でMn-CO錯体部分の構造が維持されていることがわかった。 1 H NMR and FT-IR spectra of CORM401-E are shown in FIGS. As a result of the FT-IR spectrum measurement shown in Fig. 2, CORM401-E had a carbonyl group band at the same position as CORM401, indicating that the structure of the Mn-CO complex portion was maintained before and after the reaction.
(2)CORM401-Eの溶液中におけるCO放出挙動
CORM401-EからのCO放出挙動をhemoCDアッセイによって測定した。下記式にhemoCDを示す。hemoCDの酸素付加体(oxy-hemoCD)のPBS溶液をラットの静脈中に投与すると、循環中にすみやかに血中のCOを捕捉して尿中へと排出されるが、このCO排出は定量的であり、十分量のhemoCD量を連続的に投与することによって、体内で常時生産されるCOを継続的に除去することが可能である。かかるhemoCDの性質を利用し、細胞や組織内に含まれる微量COを定量するために確立したアッセイがhemoCDアッセイである(Minegishi, S.; Yumura, A.; Miyoshi, H.; Negi, S.; Taketani, S.; Motterlini, R.; Foresti, R.; Kano, K.; Kitagishi, H. J. Am. Chem. Soc. 2017, 139, 5984-5991.)。
(2) CO release behavior in solution of CORM401-E
CO release behavior from CORM401-E was measured by hemoCD assay. hemoCD is shown in the following formula. When a PBS solution of hemoCD oxygenate (oxy-hemoCD) was administered intravenously to rats, it quickly captured blood CO in the circulation and excreted it into the urine, but this CO excretion was quantitative. By continuously administering a sufficient amount of hemoCD, it is possible to continuously remove CO that is constantly produced in the body. The hemoCD assay is an assay that has been established to quantify trace amounts of CO contained in cells and tissues using the properties of hemoCD (Minegishi, S.; Yumura, A.; Miyoshi, H.; Negi, S. Taketani, S.; Motterlini, R.; Foresti, R.; Kano, K.; Kitagishi, HJ Am. Chem. Soc. 2017, 139, 5984-5991.).
結果を図３に示す。(a)は37℃、0.1%DMSOを含むPBS中におけるCORM401-E(1μM)から放出されるCOによるhemoCD(7μM)のUVスペクトル解析図である。(b)はhemoCDアッセイにより測定されたCORM401-Eから放出される時間経過に伴うCO濃度である。測定の結果、1モルのCORM401-Eからは3モル当量のCOが溶液中において放出されることが明らかとなった。この数値は既存のCORMでありCORM401-Eの前駆体であるCORM401と同等の値である。 The results are shown in FIG. (a) is a UV spectrum analysis diagram of hemoCD (7 µM) by CO released from CORM401-E (1 µM) in PBS containing 0.1% DMSO at 37°C. (b) CO concentration over time released from CORM401-E measured by hemoCD assay. As a result of the measurement, it was revealed that 3 molar equivalents of CO were released from 1 mol of CORM401-E in the solution. This value is equivalent to CORM401, which is an existing CORM and a precursor of CORM401-E.
(3)CORM401及びCORM401-Eの細胞内CO送達効率に関する検討
CORM401及びCORM401-EをHeLa細胞の培地に50 μmol/Lの濃度で加えて2時間培養後、培地を除去し、細胞を洗浄後、細胞内に取り込まれたCO量をhemoCDアッセイによって測定した。その結果を図４に示す。その結果、CORM-401-EはCORM-401と比較して約5.4倍の細胞内CO送達量となった。
(3) Study on intracellular CO delivery efficiency of CORM401 and CORM401-E
CORM401 and CORM401-E were added to the HeLa cell medium at a concentration of 50 μmol/L and cultured for 2 hours. After removing the medium and washing the cells, the amount of CO taken into the cells was measured by hemoCD assay. The results are shown in FIG. As a result, CORM-401-E delivered about 5.4 times more intracellular CO than CORM-401.
(4)CORM401-Eの基本的物性について
CORM401-Eは、上述したように、既存のCORM401から手軽な合成反応によって容易に高収率で得られる。CORM401-Eは黄色粉末であり、固体状態で保存する分には高い安定性を示す。CORM401-Eはカルボキシ基をエステル化しているために水に難溶性を示すが、生化学実験用DMSOには高い溶解性を示す。CORM401-EのDMSO溶液は比較的高濃度においても細胞毒性を示さない。そのためCORM401-Eは例えば細胞内CO送達ツール試薬として汎用性が高い。
(4) Basic physical properties of CORM401-E
As described above, CORM401-E can be easily obtained in high yield from existing CORM401 by a simple synthetic reaction. CORM401-E is a yellow powder and exhibits high stability when stored in the solid state. CORM401-E is poorly soluble in water due to the esterification of the carboxy group, but it is highly soluble in DMSO for biochemical experiments. CORM401-E in DMSO is not cytotoxic even at relatively high concentrations. Therefore, CORM401-E is highly versatile as an intracellular CO delivery tool reagent, for example.
抗炎症疾患の治療薬やCOを細胞内へ送達するための試験化合物として利用できる。 It can be used as a therapeutic drug for anti-inflammatory diseases and as a test compound for delivering CO into cells.
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