JP7366074B2 - 3”,5”-ジアルコシベンゾイル-3’-アミノ-3’-デオキシアデノシン-5’-三リン酸及びその医薬用途 - Google Patents
3”,5”-ジアルコシベンゾイル-3’-アミノ-3’-デオキシアデノシン-5’-三リン酸及びその医薬用途 Download PDFInfo
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
- C07H1/04—Introducing polyphosphoric acid radicals
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Description
(a)以下の化合物1と、
(b)式(III)の化合物を5'-リン酸化して、式(I)の化合物を得ること
を含む。式(I)の化合物は、塩、溶媒和物、又は配位錯体として単離されてもよく、又は単離後に塩、溶媒和物、又は配位錯体に転化されてもよい。
1.式(I)の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグ:
2.R1及びR2はメチルである、実施形態1に記載の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグ。
3.前記化合物が次式のナトリウム塩である、実施形態1に記載の化合物:
5.薬学的に許容されるキャリアと、上記いずれかの実施形態に記載の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグとを含む医薬組成物。
6.P2X3受容体アンタゴニスト又はP2X2/3受容体アンタゴニストによって仲介される呼吸器疾患を治療する方法であって、当該治療を必要とする対象に、上記いずれかの実施形態に記載の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグの治療有効量を投与することを含む方法。
7.前記呼吸器疾患が咳関連呼吸器疾患である、実施形態5に記載の方法。
8.前記咳関連呼吸器疾患が慢性閉塞性肺疾患(COPD)、気管支けいれん又は喘息である、実施形態5又は6に記載の方法。
9.前記呼吸器疾患が亜急性咳嗽、慢性咳嗽、治療抵抗性咳、特発性慢性咳、上気道感染症に関連する咳、ウイルス感染後の咳、医原性咳、特発性肺線維症又は喫煙若しくは気管支炎の形態に関連する咳である、実施形態6~8のいずれかに記載の方法。
10.式(I)の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグにおけるR1及びR2がメチルである、実施形態6~9のいずれかに記載の方法。
11.膀胱の障害を治療する方法であって、当該治療を必要とする対象に、実施形態1~3のいずれかに記載の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグの治療有効量を投与することを含む方法。
12.前記膀胱の障害が膀胱過活動又は尿失禁である、実施形態11に記載の方法。
13.前記膀胱過活動が、尿意切迫感、頻尿、膀胱容量と排尿閾値の変化、不安定な膀胱収縮、括約筋痙縮、排尿筋反射亢進及び排尿筋不安定性の1つ以上を含む、実施形態11又は12に記載の方法。
14.前記膀胱の障害が間質性膀胱炎である、実施形態11~13のいずれかに記載の方法。
15.式(I)の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグにおけるR1及びR2がメチルである、実施形態11~14のいずれかに記載の方法。
16.疼痛を治療する方法であって、当該治療を必要とする対象に、実施形態1~3のいずれかに記載の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグの治療有効量を投与することを含む方法。
17.前記疼痛が侵害受容性疼痛である、実施形態16に記載の方法。
18.前記疼痛が神経因性疼痛である、実施形態16又は17に記載の方法。
19.式(I)の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグにおけるR1及びR2がメチルである、実施形態16又は17に記載の方法。
20.次式(I):
の化合物の製造方法であって、
(a)以下の化合物1と、
(b)式(III)の化合物を5'-リン酸化して、式(I)の化合物を得ること
を含む方法。
21.R1及びR2がメチルである、実施形態20に記載の方法。
別段の定義がない限り、本明細書で使用される全ての技術用語及び科学用語は、本発明が関係する当業者によって一般に理解されるのと同じ意味を有する。本明細書に記載されているものと類似又は均等の任意の方法及び材料を本発明の試験の実施に使用することができるが、好ましい材料及び方法が本明細書に記載される。本発明を説明及び特許請求する際に、以下の用語が使用される。
2’,5’-ビス-O-(t-ブチルジメチルシリル)-β-D-アデノシン(2)の合成
2Lの丸底フラスコ中において、TBDMSCl(169.2g、1.12mol)を、アデノシン(100g、0.37mol)のピリジン(800mL)懸濁液に加え、この混合物を室温で48時間撹拌した。反応のTLC(EtOAc:ヘキサン=2:1)は、3つのスポットを示した:2’、3’、5’-トリス-O-(t-ブチルジメチルシリル)-β-D-アデノシン(上のスポット、Rf=0.58)、2’、5’-トリス-O-(t-ブチルジメチルシリル)-β-D-アデノシン(中央のスポット、Rf=0.36)、3’、5’-トリス-O-(t-ブチルジメチルシリル)-β-D-アデノシン(下のスポット、Rf=0.19)。溶媒を蒸発させ、粗生成物をCH2Cl2に溶解し、氷冷した4%HClで洗浄した。水層を分離した後、有機層を飽和NaHCO3、H2O、ブラインで洗浄し、無水Na2SO4で乾燥させた。溶媒を蒸発させた後、粗製の白色固体をCH2Cl2(600mL)に溶解し、シリカゲルカラムクロマトグラフィー(部分的に、330gのISCOカラム、ヘキサン/EtOAc-0~100%EtOAc)で精製した。3回のカラムクロマトグラフィー精製後、生成物が豊富な画分の混合物を合わせて濃縮した。CHCl3/Et2Oからの再結晶により、所望の生成物(2)を純粋な白色固体として得た。複数回の再結晶により、70gの所期生成物(2)(38%)が得られた。
2Lの丸底フラスコ中において、ピリジン(19.5mL、242.4mmol)とAc2O(11.5mL、121.2mmol)を、CrO3(12.1g、0.12mol)のCH2Cl2(400mL)氷冷懸濁液に添加し、茶色のスラリーを均一になるまで30分間撹拌し、次に室温にまで加温した。化合物(2)(30g、60.6mmol)のCH2Cl2(300mL)溶液を添加し、撹拌を2時間続けた。TLCは、反応が完了したことを示した(Rf=0.41、EtOAc:ヘキサン=2:1)。反応混合物を冷EtOAc(2L)に注ぎ、濾過した。濾液を飽和NaHCO3、H2O、ブラインで洗浄し、無水Na2SO4で乾燥させた。溶媒を蒸発させた後、固体生成物を沈殿させ、濾過して、22.4gの所期生成物(3)を得た。濾液を濃縮し、シリカゲルクロマトグラフィー(ISCO 220gカラム、ヘキサン/EtOAc-0~100%EtOAc)で精製して、2.3gの生成物を得た。白色固体生成物(3)の合計収量は24.7g(82%)であった。
1Lの丸底フラスコ中において、ケトン(3)(24.7g、50.1mmol)のTHF(400mL)氷冷溶液に、NaBH(OAc)3(21.2g、100.1mmol)を添加し、この混合物を室温で72時間撹拌した。TLCは不完全な反応を示し、まだいくらかの出発物質が残っていた(Rf=0.36、EtOAc:ヘキサン=2:1)。溶媒を蒸発させ、粗生成物をEtOAcに溶解し、飽和NaHCO3、H2O、ブラインで洗浄し、無水Na2SO4で乾燥させた。溶媒を蒸発させた後、粗生成物をシリカゲルクロマトグラフィー(ISCO 220gカラム、ヘキサン/EtOAc-0~100%EtOAc)で精製した。還元中に生成された立体異性体(2)を除去するために、複数回のカラム精製が必要であった。13.5gの白色固体生成物(4)が得られた(54%)。
1Lの丸底フラスコ中において、TfCl(3.2mL、30.1mmol)を、(4)(13.5g、27.3mmol)及びDMAP(10g、81.8mmol)のCH2Cl2(250mL)氷冷溶液に加えた。この混合物を15分間撹拌した。TLCは不完全な反応を示し、まだいくらかの出発物質が残っていた(Rf=0.5、EtOAc:ヘキサン=2:1)。2回目分のTfCl(0.7mL、6.5mmol)を加え、30分間撹拌を続けた。反応物を分割し(氷冷1%AcOH/CH2Cl2水溶液)、水層をCH2Cl2で抽出した。一緒にした有機相を氷冷飽和NaHCO3、氷冷ブラインで洗浄し、無水Na2SO4で乾燥させた。溶媒を蒸発させた後、このオフホワイトのフォーム生成物を次のステップで直接使用した。
化合物(5)(6.9g、13.2mmol)のMeOH(300mL)溶液を、10%Pd/C(1.0g)の存在下において大気圧で一晩水素化(H2バルーン)した。この混合物をセライトのパッドを通して濾過した。溶媒を蒸発させた後、オフホワイトの固体生成物(6)が得られた(6.4g、97%)。
3,5-ジメトキシ安息香酸(7)(2.4g、12.9mmol)の無水DMF(100mL)溶液に、HBTU(4.9g、12.9mmol)を加え、この混合物を室温で30分間撹拌した。反応物を氷水浴で冷却しながら、化合物(6)(6.4g、12.9mmol)のDMF(50mL、無水)溶液を加え、続いてDIPEA(4.5mL、25.9mmol)を加えた。反応物を一晩撹拌し、室温まで加温した。TLCは反応の完了を示した(Rf=0.5、EtOAc:ヘキサン=2:1)。反応物を濃縮し、粗生成物をEtOAcに溶解し、飽和NaHCO3、H2O、ブラインで洗浄し、無水Na2SO4で乾燥させた。溶媒を蒸発させた後、粗生成物をシリカゲルクロマトグラフィー(ISCO 120gカラム、ヘキサン/EtOAc-0~100%EtOAc)で精製した。生成物が豊富な混合物画分を合わせて濃縮した。EtOAc/ヘキサンからの再結晶を行い、純粋な白色固体(8)が得られた(6.8g、80%)。
(8)(7.8g、11.8mmol)及びNH4F(3.9g、106.5mmol)のMeOH(600mL)溶液を、60℃の油浴中で12時間撹拌した。この透明な反応溶液は、1時間の加熱後に濁り、白色のスラリーに変化した。反応物を室温にまで冷却し、固体を濾過した。純粋な白色の固体生成物(9)が得られた(4.6g、90%)。
POCl3(0.4mL、4.6mmol)を化合物(9)(1g、2.3mmol)のリン酸トリエチル(30mL)氷冷溶液に加え、この反応混合物を0~4℃で3時間撹拌して、ジクロロホスホリデート中間体(10)得た。
テトラトリエチルアンモニウムホスフェート(11)(1.1g、0.93mmol)のMeOH(3.5mL)溶液に、1MのNaIのアセトン(9.5mL、9.3ミリモル)溶液を加えた。攪拌中に、白色の固体が沈殿した。さらに10mLのアセトンを加え、白色のスラリーを10分間撹拌した。混合物を遠心分離管に移し、遠心分離した(2分、3000rpm)。溶媒をデカントした。さらに10mLのアセトンを加えて固体を洗浄し、遠心分離し、デカントした(2回以上繰り返した)。白色の固体を真空下で乾燥させて、730mgのDT-0111(94%)を得た。
本発明の化合物は、塩の形態をとることができる。「塩」という用語は、本発明の化合物である遊離酸又は遊離塩基の付加塩を包含する。用語「薬学的に許容される塩」とは、製薬用途での有用性を提供する範囲内の毒性プロファイルを有する塩をいう。それでもなお、薬学的に許容されない塩は、例えば本発明の化合物の合成、精製又は処方の過程における有用性など、本発明の実施における有用性を有する高い結晶化度などの特性を有することがある。脱プロトン化に利用できる酸性水素の数に応じて、モノアニオン塩とポリアニオン塩の両方が考えられる。
本発明の化合物は、医薬組成物の形態で投与することができる。薬学的に許容されるキャリアと、式(I)の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグとを含む医薬組成物を製造することができる。このような製剤中の有効成分又は薬剤は、製剤の0.1~99.99重量パーセントを占めることができる。「薬学的に許容されるキャリア」とは、製剤の他の成分と相溶性があり、被投与者に有害ではない任意のキャリア、希釈剤又は賦形剤を意味する。
式Iの化合物は、その薬学的に許容される塩を含めて、経口、直腸、舌下、エアロゾル及び粉末吸入、並びに非経口投与を含む任意の経路によって投与することができる。非経口投与としては、例えば、静脈内、筋肉内、動脈内、腹腔内、鼻腔内、気管内(例えば、吸入器による)、膀胱内(例えば、膀胱へ)、皮内、経皮、局所又は皮下投与が挙げられる。また、本発明の範囲内で意図されるのは、制御された処方での患者の体内への薬物の点滴注入であり、薬物の全身的又は局所的放出が後で起こる。例えば、薬物は、循環器への制御された放出のために、又は局所部位への放出のために、貯蔵部に局在化できる。
本発明の別の実施形態によれば、治療を必要とする対象の呼吸器疾患を治療するための方法が提供され、ここで、呼吸器症状は、P2X3R及び/又はP2X2/3Rの活性化によって仲介される。したがって、本発明の化合物は、P2X3R及び/又はP2X2/3Rアンタゴニストの投与によって仲介できる呼吸器障害の治療のために有用であると考えられる。治療方法は、そのような治療を必要とする対象に、式(I)の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグの治療有効量を投与することを含む。
P2X3R及びP2X2/3Rは、一次求心性神経の末梢及び中央末端の両方に位置し、膀胱の様々な感覚機能に関与している(Khakh及びnorth, Nature 442:527-532, 2006)。膀胱感覚には、膀胱求心性C線維にあるP2X3/P2X2/3受容体のATPによる活性化が必要である。
P2X3Rサブユニットは、皮膚、関節、中空器官を含むほとんどの組織及び器官系のC線維及びAδ線維の一次求心性ニューロンで優先的かつ選択的に発現するところ、これは、人体の疼痛感知システムに対する高度な特異性を示唆する。したがって、P2X3含有受容体の活性化を遮断又は阻害する本発明の化合物などの化合物は、ATPによるこれらの線維の活性化を遮断し、それによって疼痛刺激を遮断するのに役立つ。したがって、治療を必要とする対象に、式(I)の化合物、又はその薬学的に許容される塩、溶媒和物、配位錯体若しくはプロドラッグの治療有効量を投与することを含む、疼痛の治療方法が提供される。
ノースカロライナ大学薬理学部(PDSP)が試験管内で実施した機能アッセイでは、DT-0111は次の受容体でアゴニスト又はアンタゴニストとして作用しないことが示されている:P2Y2、P2Y4、P2Y6、P2Y11、P2Y12、P2Y13及びP2Y14。これらのアッセイを、Kroezeらが提唱する、新薬の開発につながるヒトGPCRomeの調査のためのオープンソースリソースとして記載されているPRESTO-Tango法を利用して実施した(Nat. Struct. Mol. Biol. 2015 May; 22(5):362-9)。
以下のアッセイは、式(I)の化合物のP2X2/3受容体拮抗作用を実証するものである。
神経支配されたモルモット肺標品を、Undem BJ, Chuaychoo B, Lee MG, Weinreich D, Myers AC, Kollarik M. Subtypes of vagal afferent C-fibres in guinea-pig lungs. J Physiol 2004; 556: 905-917及びWeigand LA, Ford AP, Undem BJ. A role for ATP in bronchoconstriction-induced activation of guinea pig vagal intrapulmonary C-fibres. J Physiol 2012; 590: 4109-4120に記載されているように調製した。Undem外、及びWeigand外の内容は、神経支配されたモルモット肺標品の準備の目的で本明細書において援用される。ATP(10μm;1ml、気管と肺動脈にゆっくりと注入)に対する応答を、それが誘発した活動電位の数として評価した。15分間隔の2つのコントロール応答を記録した。最初の応答と2番目の応答の間で誘発された活動電位の数に違いはなかった(p>0.1)。続いて、DT-0111の濃度を上げながら、気管と肺動脈の両方を介して肺を15分間灌流し、ATPチャレンジを繰り返した。データを、誘発された活動電位の総数と、任意の1sビンで誘発された最も多くの活動電位によって測定されたピーク周波数(Hz)として定量化した。DT-0111を10mM溶液として蒸留水中で調製し、アリコートを-20℃で凍結保存(1~5日)した。
DT-0111は、生体外で神経支配されたモルモット肺標品の節状神経節迷走神経感覚神経終末に及ぼすATP(10μm)の効果に拮抗することが実証された。図5の上部では、神経活動電位(AP)記録の典型的な例が示されている。左は、ATPによって誘発されたAPのバーストである(コントロール)。中央では、DT-0111はATPの効果を著しく抑制している。右は、30分のDT-0111ウォッシュアウト後のATPの効果の回復である。図5の下の部分は、DT-0111(1mM)の非存在下(ATP)、存在下(ATP+DT)、及びウォッシュアウト後(ATP+ウォッシュアウト)に記録されたAPの数を示す。矢印はATPの投与を示す。
オスのDunkin-Hartleyモルモット(GP)(220~250g、Charles River)を14日間隔離した。収容室を常に換気し、温度を23℃に保持した。実験当日のGPの平均体重は336.0±9.9gであった。以前に公開されたように、ケタミン+キシラジン(40~80mg/kg+5~10mg/kg;IM)の混合物を使用して麻酔を誘発した((Zhuang, et al., "High-Frequency Electrical Stimulatino of Cervical Vagi Reduces Airway Response to Methacholine," World J. of Respirology 2013 July 28; 3(2): 11-19)。耳のつまみによって呼吸数が変化した場合、及び/又は心拍数の加速が現れた場合には、必要に応じて追加の麻酔薬用量(元の用量の1/4~1/2)を投与した。体温を直腸体温計で継続的に監視し、加熱パッドとランプを使用して約36.5℃に維持した。気管を喉頭下にカニューレ挿入し、空気圧計に接続して、差圧トランスデューサー(ML141、AD Instruments、Castle Hill、Australia)を介して気流を測定した。この動物について、実験全体を通して窒素中の30%酸素のガス混合物に曝露し、CO2(PETCO2)の終末潮圧を~40トルに維持するように調整した、2.5mlの1回呼吸量で、70~75呼吸/分の一定頻度(fR)で換気した。エアロゾルチャレンジに使用されるATP(Sigma-Aldrich)の溶液を、粉末を0.9%食塩水(NaCl)溶液に溶解することにより、使用直前に新たに調製した。食塩水及び試験溶液を、振動メッシュネブライザー(Ireland Ltd.、Galway Ireland、AG-AL1000)によってエアロゾル化し、ヘッドチャンバーに直接送った。ネブライザーのリザーバーの容量は~10mlであった。送達されたエアロゾルの出力速度は0.5ml/minで、空気力学的質量中央径は3.7μmであった(製造元の公称値)。ネブライザーによって生成されたエアロゾルを気流(1000ml/min)と混合し、プラスチックシリンダー(直径16mm)に流し込んだ。後者に、人工呼吸器の吸気口(直径4.5mm)を緩く覆い、それによってGPを人工呼吸器から供給されるエアロゾルと共に換気した。
エアロゾル曝露を2分間続行し、その間に、6mgのDT-0111を2000mlの気流(1000ml/min)と混合した。動物の呼吸は300ml/2分であった。したがって、2分間の暴露中に気道及び肺に吸入されたDT-0111のおおよその量は6mg×(300÷2000)=0.9mgであった。平均体重(336.0g)に基づけば、吸入されたDT-0111は2.6mg/kgであった。
この試験を6匹のモルモットで実行した。収容室を常に換気し、温度を約23℃に保った。検疫後、動物を個別に、全身非拘束プレチスモグラフチャンバー(モデルPLY3215、Buxco Electronics Inc.、Troy、NY)に1日1回、2日間連続して約40分間入れてから、咳試験を行った。咳の試験の前に、全てのモルモットの体重を測定した。
プレチスモグラフチャンバーの上部を、ネブライザーによって取り付けられたプラスチックチューブに接続した。ネブライザーコントローラーによって駆動される正常酸素圧空気をチャンバーに流入させ、バイアスフローレギュレーターによって流入及び流出量のバランスが取れた状態(2.0L/分)で吸引した。咳を検出するために、マイクシステムをチャンバーの屋根に取り付け、音を録音した。動物の体の姿勢を監視するために、ビデオカメラをチャンバーの外側に配置した。空気の流れを記録するために、Buxcoニューモタコグラフ(差圧トランスデューサー)をチャンバーに取り付けた。ビデオカメラ、マイク、及び圧力トランスデューサーによって生成された全ての信号を、PowerLab/8sp(モデルML 785; ADInstruments Inc.、Colorado Springs、CO)と、LabChart Pro7ソフトウェアを備えたコンピュータによって継続的に増幅及び記録した。
以前に報告された典型的な咳反応(Girard et al., Eur Respir J, 1995; Blasko et al., American Journal of Advanced Drug Delivery. 5:131-138, 2017;Corboz et al., Journal of Pharmacology and Experimental Therapeutics. 363: 348-357, 2017)は、次の同時出現によって定義された:1)気流の一時的の大きな変化(急速な吸気とそれに続く急速な呼気);2)周波数スペクトルにおいてピーク電力密度が1~2kHzの典型的な咳音(3.5~6.5kHzではくしゃみ);及び3)動物の体(頭)の姿勢と動き。
Claims (21)
- 次式(I)の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体:
- R1及びR2がメチルである、請求項1に記載の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体。
- 前記化合物が次式のナトリウム塩である、請求項1に記載の化合物:
- 薬学的に許容されるキャリアと、請求項1に記載の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体とを含む医薬組成物。
- 薬学的に許容されるキャリアと、請求項2に記載の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体とを含む医薬組成物。
- P2X3受容体又はP2X2/3受容体によって仲介される呼吸器疾患を治療するための医薬組成物であって、請求項1に記載の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体を含む医薬組成物。
- 前記呼吸器疾患が咳関連呼吸器疾患である、請求項6に記載の医薬組成物。
- 前記咳関連呼吸器疾患が慢性閉塞性肺疾患(COPD)、気管支けいれん又は喘息である、請求項7に記載の医薬組成物。
- 前記呼吸器疾患が亜急性咳嗽、慢性咳嗽、治療抵抗性咳、特発性慢性咳、上気道感染症に関連する咳、ウイルス感染後の咳、医原性咳、特発性肺線維症又は喫煙若しくは気管支炎の形態に関連する咳である、請求項6に記載の医薬組成物。
- 式(I)の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体におけるR1及びR2がメチルである、請求項7~9のいずれかに記載の医薬組成物。
- 膀胱の障害を治療するための医薬組成物であって、請求項1に記載の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体を含む医薬組成物。
- 前記膀胱の障害が膀胱過活動又は尿失禁である、請求項11に記載の医薬組成物。
- 前記膀胱過活動が、尿意切迫感、頻尿、膀胱容量と排尿閾値の変化、不安定な膀胱収縮、括約筋痙縮、排尿筋反射亢進及び排尿筋不安定性のうちの1つ以上を含む、請求項12に記載の医薬組成物。
- 前記膀胱の障害が間質性膀胱炎である、請求項11に記載の医薬組成物。
- 式(I)の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体におけるR1及びR2がメチルである、請求項12~14のいずれかに記載の医薬組成物。
- 疼痛を治療するための医薬組成物であって、請求項1に記載の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体を含む医薬組成物。
- 前記疼痛が侵害受容性疼痛である、請求項16に記載の医薬組成物。
- 前記疼痛が神経因性疼痛である、請求項16に記載の医薬組成物。
- 式(I)の化合物、又はその薬学的に許容される塩、溶媒和物若しくは配位錯体におけるR1及びR2がメチルである、請求項16又は17に記載の医薬組成物。
- 次式(I)の化合物:
の製造方法であって、
(a)次の化合物1と、
次式(IIa)の化合物
(b)式(III)の化合物を5'-リン酸化して、式(I)の化合物を得ること
を含む方法。 - R1及びR2がメチルである、請求項20に記載の方法。
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