JP2010512314A - 疾患を治療するためのgabaアナログのプロドラッグの使用 - Google Patents
疾患を治療するためのgabaアナログのプロドラッグの使用 Download PDFInfo
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Abstract
【選択図】 なし
Description
R1は、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択され;
R2およびR3は、それぞれ独立して、水素、アルキル、置換アルキル、アルコキシカルボニル、置換アルコキシカルボニル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、カルバモイル、置換カルバモイル、シクロアルキル、置換シクロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択されるか、またはR2およびR3は、それらが結合している炭素原子と一緒になって、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、および置換シクロヘテロアルキル環から選択される環を形成し; そして
R4は、アシル、置換アシル、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択される。
2つの文字または記号の間に存在するものではないダッシュ(「-」)は、部分(moiety)または置換基の結合点を示すために用いられる。例えば、-CONH2は炭素原子を介して結合される。
R6は水素であるか、またはR6とR10は、それらが結合している原子と一緒になって、アゼチジン、置換アゼチジン、ピロリジン、および置換ピロリジン環から選択される環を形成し;
R7およびR10は、独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択され; そして
R8およびR9は、独立して、水素、アルキル、置換アルキル、アシル、置換アシル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択されるか、またはR8とR9は、それらが結合している炭素原子と一緒になって、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、および架橋シクロアルキル環から選択される環を形成する。
R1は、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択され;
R2およびR3は、独立して、水素、アルキル、置換アルキル、アルコキシカルボニル、置換アルコキシカルボニル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、カルバモイル、置換カルバモイル、シクロアルキル、置換シクロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択されるか、またはR2とR3は、それらが結合している炭素原子と一緒になって、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、および置換シクロヘテロアルキル環から選択される環を形成し; そして
R4は、アシル、置換アシル、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択される。
GABAアナログのプロドラッグの合成方法は、構造式(I)、(II)、(III)、および(IV)の化合物の合成方法を含めて、Gallopら、PCT国際公開番号WO 02/100347、Gallopら、米国出願公開番号2004/0077553、およびBhatら、米国出願公開番号2005/0070715(それぞれが本明細書にその全体を参考として組み込まれる)に開示されている。また、GABAアナログのプロドラッグの他の合成方法も開示されている(Bryansら、PCT国際公開番号WO 01/90052; 英国出願GB 2,362,646; ヨーロッパ出願EP 1,201,240 および 1,178,034; Yatvinら、米国特許第6,024,977号; Gallopら、PCT国際公開番号WO 02/28881; Gallopら、PCT国際公開番号WO 02/28883; Gallopら、国際公開番号WO 02/28411; Gallopら、PCT国際公開番号WO 02/32376; ならびにGallopら、PCT国際公開番号WO 02/42414を参照のこと)。
特定の実施形態において、GABAアナログのプロドラッグまたはその医薬組成物は、片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患の患者に投与することができる。GABAアナログのプロドラッグまたはその医薬組成物が片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患を治療するのに適しているかは、当業者に公知の方法で確認することができる。
本開示により提供される医薬組成物は、少なくとも1種の式(I)、式(II)、式(III)、および/または式(IV)の化合物と、少なくとも1種の製薬上許容されるビヒクルを含有する。医薬組成物は治療上有効な量の式(I)、式(II)、式(III)、および/または式(IV)の化合物と、少なくとも1種の製薬上許容されるビヒクルを含むことができる。特定の実施形態では、医薬組成物は2種以上の式(I)、式(II)、式(III)、および/または式(IV)の化合物を含んでいてもよい。製薬上許容されるビヒクルには希釈剤、補助剤(アジュバント)、賦形剤、および担体が含まれる。
本開示により提供される医薬組成物は単位剤形に製剤化することができる。単位剤形は、治療を受ける患者のための単位用量として適する、物理的に離散した単位をさし、各単位は意図した治療効果を生むように計算された所定量の式(I)、式(II)、式(III)、または式(IV)の化合物少なくとも1種を含有する。単位剤形は1日1回投与、1日1〜2回投与、または1日複数回投与、例えば1日2〜4回投与用でありうる。1日複数回投与を用いる場合、単位用量は各回ごとに同じでも異なっていてもよい。1つ以上の剤形が1回分の用量を含んでいてもよく、それを単一の時点でまたはある期間の間に患者に投与することができる。
片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患から選択される疾患の治療方法は、かかる治療が必要な患者に、少なくとも1種の式(I)、式(II)、式(III)、または式(IV)のGABAアナログプロドラッグ、または前記化合物のいずれかを含む医薬組成物を投与することを含んでなる。
特定の実施形態において、少なくとも1種の式(I)、式(II)、式(III)、または式(IV)のGABAアナログプロドラッグ、または前記プロドラッグのいずれかを含む医薬組成物は、異なる式(I)、式(II)、式(III)、または式(IV)のGABAアナログプロドラッグを含めた少なくとも1種の他の治療薬と共に、併用療法で使用することができる。式(I)、式(II)、式(III)、または式(IV)のGABAアナログプロドラッグ、または前記プロドラッグのいずれかを含む医薬組成物と、追加の治療薬は、相加的に作用するか、またある実施形態では相乗的に作用することができ、結果的に、これらの治療薬の組合せは、例えば、より効果的で、より安全であり、かつ/またはより少ないもしくはより軽い副作用をもたらす。特定の実施形態では、式(I)、式(II)、式(III)、または式(IV)のGABAアナログプロドラッグ、または前記プロドラッグのいずれかを含む医薬組成物は、別の治療薬の投与と同時に投与することができる。特定の実施形態では、式(I)、式(II)、式(III)、または式(IV)のGABAアナログプロドラッグ、または前記プロドラッグのいずれかを含む医薬組成物は、別の治療薬の投与前または投与後に投与することができ、したがって重複するスケジュールのレジメンをもち得る。追加の治療薬は、片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患を治療するのに有効であってもよく、片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患の少なくとも1つの症状を治療するのに有効であってもよく、片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患を治療するために式(I)、式(II)、式(III)、または式(IV)のGABAアナログプロドラッグを投与することに伴う副作用を軽減するのに有効であってもよく、あるいは片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患以外の疾患、障害、または症状を治療するのに有効であってもよい。式(I)、式(II)、式(III)、または式(IV)の化合物が片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患を治療するための追加の治療薬と一緒に投与される特定の実施形態では、活性薬剤のそれぞれを、単独で用いるときより低用量で用いることができる。
特定の実施形態において、本開示により提供されるGABAアナログプロドラッグおよびその医薬組成物は、喘息の治療のために、喘息(または、ある実施形態では喘息と関連した疾患、障害、または症状)の治療に有効であると知られているまたは考えられる療法または別の治療薬と併用して、患者に投与することができる。喘息の治療に有用な薬物の例としては、以下が挙げられる:アルブテロール、アミノフィリン、ベクロメタゾン、ビトルテロール、ブデソニド、クロモリン、エフェドリン、エピネフリン、フルニソリド、フルチカゾン、ホルモテロール、ヒドロコルチゾン、イソプロテレノール、レバルブテロール、メチルプレドニゾロン、プレドニゾロン、プレドニゾン、ピルブテロール、メタプロテレノール、ラセエピネフリン(racepinephrine)、オマリズマブ(omalizumab)、オキシトリフィリン、モメタゾン、モンテルカスト、ネドクロミル、オキシトリフィリン、ピルブテロール、サルメテロール、テルブタリン、テオフィリン、トリアムシナロン(triamcinolone)、ザフィルルカスト(zafirlukast)、およびジロートン(zileuton)。
以下の実施例を参考にすることで本発明をさらに明確に説明するが、これらの実施例は、式(I)、式(II)、式(III)、および式(IV)のGABAアナログプロドラッグの合成、少なくとも1種のGABAアナログプロドラッグを含む徐放性剤形の製造、ならびに少なくとも1種の式(I)、式(II)、式(III)、または式(IV)のGABAアナログプロドラッグを投与することを含む、片頭痛、線維筋痛症、筋萎縮性側索硬化症、過敏性腸症候群、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患の治療方法を記載している。本発明の範囲から逸脱することなく、材料と方法の両方に対して多くの修飾が可能であることは、当業者に明らかだろう。実施例8〜13は机上のことである。
工程A: 1-{[(α-クロロエトキシ)カルボニル]アミノメチル}-1-シクロヘキサン酢酸
ジクロロメタン(1.6L)を含む5リットルの三口丸底フラスコにガバペンチン(120.4g, 0.704mol)を加え、続いてトリエチルアミン(294mL, 2.11mol)を加えた。反応温度を15℃以下に保ちながらクロロトリメチルシラン(178mL, 1.40mol)を徐々に加えて、得られた懸濁液を30分間撹拌した。次に、クロロギ酸1-クロロエチル(100g, 0.704mol)を、温度を15℃以下に保ちながら、少しずつ加えた。添加が完了した後、追加のトリエチルアミン(88mL, 0.63mol)を加え、その結果生じた懸濁液を室温で30分間撹拌した。得られたシリルエステルを酸性の後処理によって対応する酸に変換したが、この変換は、反応混合物を水(2×1L)で洗い、続いて1N HCl (2×2L)、その後食塩水(2×500mL)で洗うことにより行った。無水硫酸ナトリウムで乾燥させ、溶媒を真空下で除去した後に粗生成物(190g)が橙色のオイルとして得られたが、これはそれ以上精製せずに工程Bで使用した。1H NMR (CDCl3, 400 MHz): δ1.41 - 1.57 (m, 10H), 1.78 (d, 3H), 2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H)。
3リットルの三口丸底フラスコにイソ酪酸(254g, 2.9mol)、続いてトリエチルアミン(395mL, 2.84mol)を加えた。この反応混合物を室温へと冷却し、上記の反応工程からの粗製の酸(190g, 0.69mol)をジクロロメタン(80mL)に溶解した溶液を、温度を30℃以下に保ちながら、制御された方法で添加した。その結果生じた淡黄色の溶液を一晩撹拌した。次に、反応混合物を1容のジクロロメタンで希釈し、水(6×500mL)、炭酸水素カリウム水溶液(3×500mL)、および食塩水(2×500mL)で洗った。無水硫酸ナトリウムで乾燥させてから溶媒を真空下で除去すると、粗生成物が暗赤色のオイル(87g)として得られた。この生成物の一部(35g)を800gのBiotageTM順相シリカゲルフラッシュカラムにローディングし、40%ジエチルエーテル-へキサン(6L)を用いて溶出した。溶媒を真空下で除去すると生成物が無色のオイル(13.5g)として得られた。粗生成物の別の35g部分を用いてこれを繰り返したところ、さらに13.5gの1-{[(α-イソブタノイルオキシエトキシ)カルボニル]アミノメチル}-1-シクロヘキサン酢酸が得られた。生成物のサンプル(25g)を70℃でヘプタン(325mL)に溶解し、続いて室温までゆっくり冷やすことにより再結晶を行った。濾過して白色結晶質の生成物(23g)を単離した。融点:63〜64℃。
工程A: 1-アミノメチル-1-シクロヘキサン酢酸アリル塩酸塩
磁気撹拌棒と500mL圧力平衡用滴下ロートを備えた乾燥3L三口丸底フラスコに窒素ガスを流し込んだ。このフラスコにガバペンチン(171g, 1.0mol)およびアリルアルコール(1L, 852g, 14.6mol)を投入し、全混合物を氷水浴中で0℃に冷却した。この撹拌溶液に塩化チオニル(225mL, 360g, 3.0mol)を1時間かけて滴下しながら加えた。反応混合物を室温で16時間撹拌し、その後エチルエーテル(2L)で希釈してから、撹拌しながら0℃に冷却した。数分後、白色結晶が生成し、これを濾過により回収した。粗生成物をエタノールとエチルエーテルの1/3(v/v)混合溶媒(2L)から再結晶すると、生成物が白色固体として得られた(220g, 収率88%)。融点: 138〜142℃。1H NMR (CD3OD, 400 MHz): δ1.36-1.54 (m, 10H), 2.57 (s, 2H), 3.05 (s, 2H), 4.61 (d, J = 6 Hz, 2H), 5.22 (dd, J = 10.4, 1.2 Hz, 1H), 5.33 (dd, J = 17.2, 1.4 Hz, 1H), 5.90-6.00 (m, 1H)。MS (ESI) m/z 212.0 (M+Cl)+。
ジクロロメタン(1L)に上記の塩酸塩(220g, 0.89mol)を溶解した溶液に、クロロギ酸1-クロロエチル(101.7mL, 132.3g, 0.92mol)を徐々に加えた。この反応混合物を0℃に冷やし、4-メチルモルホリン(205mL, 188.9g, 1.87mol)を1時間かけて少しずつ加えたが、その間温度を10℃より低く保った。生じた濁った溶液を室温で1時間撹拌した。エタノール(150mL)を加えて、反応混合物を室温で1時間撹拌した。その後、反応混合物をエーテル(2.5L)で希釈し、水(1L)および食塩水(1L)で洗った。有機相を硫酸ナトリウムで乾燥させて濃縮すると、表題化合物が淡黄色の粘性液体として得られた(282g, 収率100%)。1H NMR (CDCl3, 400 MHz): δ1.35-1.58 (m, 10H), 1.78 (d, J = 5.6 Hz, 3H), 2.32 (s, 2H), 3.22 (d, J = 6.8 Hz, 2H), 4.57 (d, J = 5.6 Hz, 2H), 5.25 (dd, J = 10.4, 1 Hz, 1H), 5.32 (dd, J = 17.2, 1.6 Hz, 1H), 5.52 (br, 1H, NH), 5.90-5.94 (m, 1H), 6.54 (q, J = 5.6 Hz, 1H)。
イソ酪酸(432mL, 391.5g, 4.4mol)と4-メチルモルホリン(488mL, 449g, 4.4mol)の混合物に、上記の工程からのクロロカルバメート(282g, 0.88mol)をイソ酪酸(432mL, 391.5g, 4.4mol)に溶解した溶液を添加した。この添加は0℃で30分間にわたり行った。生じた濁った溶液を室温で16時間撹拌した。反応混合物をエーテル(2.5L)で希釈し、水(3×500mL)、続いて10%炭酸水素カリウム水溶液(6×500mL)、その後食塩水(500mL)を用いて洗浄した。有機相を硫酸ナトリウムで乾燥させて濃縮すると、表題化合物が粘性液体として得られた(328g, 収率100%)。1H NMR (CDCl3, 400 MHz): δ1.15 (d, J = 7.2 Hz, 6H), 1.35-1.58 (m, 10H), 2.31 (s, 2H), 2.51 (m, 1H), 3.19 (d, J = 5.6 Hz, 2H), 4.56 (d, J = 5.6 Hz, 2H), 5.24 (dd, J = 10, 1 Hz, 1H), 5.32 (dd, J = 17, 1.2 Hz, 1H), 5.35 (br, 1H), 5.84-5.94 (m, 1H), 6.78 (q, J = 5.6 Hz, 1H)。MS (ESI) m/z 392.24 (M+H)+。
エタノール(500mL)中のギ酸アンモニウム(112g, 1.7mol)の撹拌した懸濁液に、上記のアリルエステル(328g, 0.88mol)を10% Pd/C (15g)と一緒に窒素雰囲気下で加えた。6時間後、触媒を濾過により除いて反応混合物の後処理を行った。触媒をエタノール(2×250mL)で洗い、濾液を合わせて蒸発させた。粗生成物をエーテル(2L)に溶解し、有機相を2N HCl (2×2L)で洗ってアンモニウム塩を酸の形態に変換し、続いて水(1L)と食塩水(1L)を用いて洗った。エーテル層を硫酸ナトリウムで乾燥させて濃縮すると、粘性液体として粗生成物が得られた(240g, 収率82%)。
3Lの丸底フラスコに加熱用の油浴、窒素入口アダプター、内部温度計、オーバーヘッド撹拌機、および還流冷却器を取り付けた。このフラスコに窒素を流し込み、酢酸エチル/ヘプタンの1/10(v/v)混合溶媒(1.2L)および上記反応からの粗生成物(240g)を投入した。生成物が溶解するまでフラスコを加熱し、その後下記の表に従って冷却した。
CuKα線を用いるBruker D8 Discover粉末X線回折装置を使って、上記の実施例1および2に従って製造した1-{[(α-イソブタノイルオキシエトキシ)カルボニル]アミノメチル}-1-シクロヘキサン酢酸の結晶サンプルの粉末X線回折図(XRPD)を得た。この装置には平行ビーム光学系と2次元HI-STARエリア検出器を取り付けた。管電圧およびアンペア数をそれぞれ40kVと40mAに設定した。平行X線ビームを直径約0.5mmのスポットサイズに減じた。エリア検出器はゴニオメーターの中心から15cmのところに配置し、角度分解能を約0.033°/ピクセルとする。この検出器は1フレーム内で2θにして35°の範囲をカバーした。X線ビームと水平サンプルプレートとの角度を4°に設定し、また、エリア検出器の中心を18°の角度に設定した。この幾何配置は1フレーム内で4.5°〜39.5°の2θの測定を可能にした。典型的な平均化時間は集められた各XRPDパターンについて3分であった。XRPD装置のキャリブレーションをするためにコランダム試料(NIST 1976)を使用した。両試料は同等の回折パターンを与えた。
上記の実施例1および2に従って製造した1-{[(α-イソブタノイルオキシエトキシ)カルボニル]アミノメチル}-1-シクロヘキサン酢酸の結晶サンプルの融点は、Electrothermal 9200融点測定装置を用いて測定したところ、63〜64℃であると決定された。
水(40mL)にガバペンチン(6.8g, 0.04mol)を溶解した溶液に、アセトニトリル(40mL)に[(1-イソブタノイルオキシエトキシ)カルボニルオキシ]スクシンイミド(10g, 0.036mol)を溶解した溶液を30分間にわたり添加した。この反応を周囲温度で3時間撹拌した。反応混合物をメチルt-ブチルエーテル(200mL)で希釈し、水(2×100mL)と食塩水(50mL)で洗浄した。有機相を分離し、無水硫酸ナトリウムで乾燥させ、濾過してから真空濃縮すると、表題化合物が白色固体として得られた(12g、定量的)。
ガバペンチンのプロドラッグである1-{[(α-イソブタノイルオキシエトキシ)カルボニル]アミノメチル}-1-シクロヘキサン酢酸 (化合物(3))を含む徐放性経口剤形は、Cundyによる米国出願公開番号2006/0141034(本明細書にその全体を参考として組み込まれる)に開示された方法に従って製造した。化合物(3)を含む経口徐放性錠剤を製造したが、この錠剤は表1に示した成分を含んでいた。
1-{[(α-イソブタノイルオキシエトキシ)カルボニル]アミノメチル}-1-シクロヘキサン酢酸(3)の安全性、耐容性、および薬物動態についての無作為化、クロスオーバー、満腹時/空腹時の単回投与試験を、健康な成人被験者において実施した。この試験には実施例6で製造した経口徐放性剤形(コーティングなし)を用いた。この試験は、ヒトにおけるこの製剤の性能を、市販のガバペンチンカプセル剤(Neurontin(登録商標), Pfizer社)と比較して評価するようにデザインされた。12人の健康な成人ボランティア(男性7人、女性5人)がこの試験に参加した。平均体重は75.6kgであった。全ての被験者は順不同に2種類の異なる治療を受けたが、治療と治療の間に1週間のウォッシュアウト(洗い出し)期間を設けた。2種類の治療は次のとおりであった:A) 一晩絶食後に実施例6の錠剤(2×600mg)の単回経口投与; および B) 高脂肪朝食後に実施例6の錠剤(2×600mg)の単回経口投与。
本開示により提供される化合物の治療活性は、神経因性疼痛のさまざまな動物モデルで、または異なるタイプの神経因性疼痛の臨床的に関連する試験で、確認することができる。神経因性疼痛の動物モデルは当技術分野で公知であり、限定するものではないが、CNSに作用して中枢の鋭敏化現象(無痛または無害の刺激から疼痛を感じる)を低下させる化合物の鎮痛作用を測定する動物モデルが含まれる。当技術分野で知られている、例えば急性疼痛のモデルであるホットプレート試験のような、他の動物モデルは、痛みのあるまたは有害な刺激が存在するときに効果的である化合物の鎮痛特性を調べるのに有用である。片頭痛の進行はてんかんの進行に似ていると考えられ(エピソード現象がてんかんエピソードの開始の土台となるため)、したがって、てんかんの動物モデルは片頭痛を治療する際の有効性を検討するのに有用であると考えられる。
下記の試験を用いてGABAアナログプロドラッグの鎮痛活性を評価することができる。試験化合物をマウスに経口投与する。同一の実験条件下で、基準物質としてモルヒネを64mg/kgでマウスに投与する。同一の実験条件下で、対照物質としてビヒクルをマウスに投与する。盲検試験で試験化合物、モルヒネ、またはビヒクルをマウスに投与する。試験化合物、モルヒネ、またはビヒクルを投与してから60分後に、Plexiglassシリンダーで囲ってある、54℃に維持した金属製ホットプレートの上にマウスを載せる (例えば、Eddy et al., J. Pharmacol. Exp. Ther. 1953, 107, 385-393を参照こと)。マウスが足をなめるのに要した時間が鎮痛活性の指数である。有効な鎮痛薬は潜伏期、つまり足をなめるまでの時間量を増加させる。最初に足をなめるまでの潜伏期を測定するが、マウスへの組織損傷を防ぐために最長時間を30秒までとする。
慢性脊髄横断ラット(chronic spinally transected rats)での反射亢進、疼痛、および筋緊張の評価は、体重270〜530gmのアルビノHoltzman系雄ラットを用いて実施する。ラットを個別にケージに収容し、実験全体を通して餌と水に常時接近できるようにする。イソフルランと酸素の混合物を4L/分の流量で用いて動物を麻酔する。
三叉神経血管系の侵害受容活性化に及ぼす試験化合物の影響は、Goadsby et al., Brain 2002, 125, 1392-1401に記載される片頭痛モデルを用いて測定する。試験化合物を含む医薬組成物をネコに投与する。陽性及び陰性対照として役立つように、ビヒクル対照をネコに投与する。ビヒクルを投与されたネコの三叉神経血管活性化と比較して、三叉神経血管活性化を抑制する化合物には有効性が示される。
あくびは、ドパミン作動性の神経伝達と結びついた行動であって、片頭痛発作中に大部分の患者に現れる行動症候群の一部である。ラットにおけるキンピロール誘発性あくびの遮断は、片頭痛症状の潜在的な拮抗薬を研究するための動物モデルとして使用されている。
下記の動物モデルを用いて、タンパク質漏出(片頭痛のニューロン作用機序の代表的な機能アッセイ)を抑制するGABAアナログプロドラッグの能力を測定することができる。
片頭痛と情動障害とてんかんの間には、ある関係が報告されている。3つの疾患は区別可能であるが、これらは全て薬理学において部分的にオーバーラップする神経系の発作性調節障害である。複雑部分発作(complex-partial seizures)のキンドリングモデルは、辺縁構造体(例えば、扁桃の基底外側の核)の繰り返された無痙攣電気刺激により誘発される脳波(EEG)の発作性パターンと組み合わさった発作の漸進的発達に基づくものである。ひとたび確立されると、その現象は何ヶ月も持続する。動物における扁桃核キンドリング発作(amygdala-kindled seizures)はヒトでの複雑部分発作と多くの特徴を共有するので、それは複雑部分発作の有用な動物モデルである (Loscher et al., Epilepsy Res. 1993, 15(3), 207-19)。扁桃核キンドリングモデルを用いることの利点は、部分発作および全般性発作の行動パラメーターとEEGパラメーターの両方を測定できることである。さらに、扁桃核キンドリングモデルは、症候性エピソードの数に関係するやり方で経時的に重症度が増していく片頭痛、情動障害、およびてんかんのような疾患を研究するのに適すると報告されている。
片頭痛を治療する際の式(I)、式(II)、式(III)、または式(IV)の化合物の有効性は、無作為化、二重盲検、プラセボ対照、パラレルグループの臨床試験を用いて評価することができる。この試験の第1の目的は、再発性の片頭痛エピソードを治療する際の、プラセボに対する試験化合物の安全性と有効性を、月(28日)ごとの片頭痛エピソード評価のベースライン相から二重盲検相までの変化に基づいて、評価することである。第2の目的は、(a) 片頭痛患者でのプラセボに対する試験化合物による治療が、治療に応答する(月ごとの片頭痛エピソード評価で50%以上減少する)被験者のパーセントに及ぼす影響を評価し、かつ(b) 月あたりの片頭痛日数、(c) 片頭痛の平均持続時間、(d) レスキュー薬物治療の使用、(e) 片頭痛による頭痛の平均重症度、(f) 片頭痛関連症状(悪心、嘔吐、光恐怖、音恐怖)の平均重症度の、ベースライン相から二重盲検相までの変化を評価すること;片頭痛治療における1回分の試験化合物を比較するための安全性および有効性データを得ること;ならびに片頭痛患者でのプラセボに対する1回分の試験化合物による治療が、健康関連クオリティ・オブ・ライフ(HRQL)およびSF-36クオリティ・オブ・ライフ尺度の片頭痛特異的尺度、ならびにHRQLと片頭痛頻度との相互関係に及ぼす影響を評価すること、である。
線維筋痛症を治療するための有効性は、当技術分野で知られている神経因性疼痛の動物モデルを用いて評価することができ、かかる動物モデルとしては、例えば、カラゲニン誘発足痛覚過敏モデル、von Freyフィラメント試験、絞扼性神経損傷、ラット神経因性疼痛のChungモデル、Hargreaves試験、冷感異痛モデル、その他の試験がある。
拘束ストレスにより誘発される排便数の増加は、過敏性腸症候群の病理学的モデルとして使用することができる (Miyata et al., J. Pharmacol. Exp. Ther 1992, 261, 297-303)。Williamsらの方法を用いて、ラットでの排便数の減少に及ぼす試験化合物の有効性を評価する (Williams et al., Gastroenterology 1988, 94, 611-621)。試験化合物をラットに投与し、1時間後、エーテル麻酔下でラットの前足を接着テープでその胴体に固定する(拘束ストレスの負荷)。拘束を加えてから1時間後、排便数を数え、その数を対照グループの数と比較する。拘束ストレスの負荷のため、対照グループのラットの排便数は有意に増加する。IBSの治療に有用性を示す化合物は、拘束ストレスによって誘導される排便数の増加を抑制するものである。
社会恐怖症のような情動障害を治療する際の化合物の有効性を評価するために動物モデルを用いることができる。
恐怖で増強された驚愕パラダイム、例えば条件恐怖刺激(conditioned fear stimulus: CFS)の存在下で増大した驚き、は中心扁桃体を巻き込むことがわかっている学習恐怖パラダイムである (例えば、Davis, Behav. Neurosci. 1986, 100, 814-824; およびHelton et al., J. Pharmacol. Exp. Ther 1998, 284, 651-660を参照のこと)。恐怖で増強された驚きは、外傷後ストレス障害や他の不安が根底にある疾患に現れる行動病理を模倣する神経学的プロセスを引き起こす。高揚した不安は知覚プロセシングを損傷し、その結果として記憶、認識、および社会的機能の低下が起こる。全般性社会恐怖症 (Stein et al., Arch. Gen. Psychiatry 2002, 59, 1027-1034) のようなヒトの症状または薬物誘導性不安の動物モデル (Sanders and Shekhar, Pharmacol. Biochem. Behav. 1995, 52, 701-706) に見られる不安惹起状態は、異常な扁桃体機能を伴う。ヒトの試験から、ベースライン時応答および恐怖で増強された応答はいずれも、ベンゾジアゼピン、アルプラゾラムなどの抗不安薬により抑制されることが実証された (Riba et al., Psychopharmacology (Berl) 2001, 157, 358-367)。ラットおよびヒトにおける恐怖増強驚愕応答の測定は、薬物の潜在的抗不安活性の指標を提供する (例えば、Belzung, Current Opinion in Investigational Drugs. 2001, 2(8), 1108-1111; および Nestler et al., Neuron, 2002, 34, 13-25を参照のこと)。したがって、これらの公知のモデルは、情動障害の治療薬としての式(I)、式(II)、式(III)、および式(IV)の化合物の有効性を確認するために使用することができる。
ラットにビヒクルまたは試験化合物を生後25日から生後70日まで投与する。10匹の無作為に選別したラット/性別/グループの歩行運動活動を生後30日(未成熟)と生後72日(成体)に測定する。生後30日と生後72日に、各ラットを、自動フォトビーム活動システム(Photobeam Activity System)を備えた靴箱形のケージに入れる。歩行運動活動を12(5分間隔)からなる60分セッションの間にモニタリングする。12(5分間隔)のそれぞれの間に生じるフォトビーム破壊の合計数を記録する。新しい環境への慣れ(habituation)の変化は、慣れについての対照対試験グループ間で3セッション間隔にわたる歩行運動活動を比較することにより評価する。情緒性は排便、排尿、立ち上がり行動、毛づくろい、および後ろもどりを含む、行動面を追跡することにより判定する (例えば、Hall, J. Comp. Physiol. Psychol., 1936, 22, 325-352; および Spyker, in Behavioral Toxicology, Ed. Weiss and Laties, Plenum Press, New York, pp 311-349, 1975を参照のこと)。機能観察評価は生後75日に、Irwin, Psychopharmacologia 1968, 13, 222-257に記載されるパラメーターに従っておこない、歩きぶり、姿勢、異常行動、および発声を評価する。
抗不安または抗うつ活性のある薬物は、鎮静、記憶喪失または他の認識障害、活動過多、活動低下などの望ましくない副作用を示すことが多い。こうした望ましくない副作用についての標準試験は、薬物を繰り返し投与した後で新しい環境に対するラットの活動および情緒性を定量化するものである。学習および記憶の面に及ぼす薬物の影響を測定するための更なる試験としてMスイム迷路(M Swim Maze)がある。
社会性相互作用試験は、抗不安特性を評価するために用いられるもう一つの試験である (例えば、File and Hyde, Pharmacol Biochem Behav 1979, Jul 11(1), 65-69を参照のこと)。
SOD1突然変異に関連したALSのマウスモデルとして、マウスが残基93にヒトスーパーオキシドジスムターゼ(SOD)突然変異グリシン.fwdarw.アラニン(SOD1)を発現するモデルが開発されている。これらのSOD1マウスは、SODの不利な性質の優性獲得を示し、ヒトALSと同様の運動ニューロン変性および機能不全を発症する (Gurney et al., Science 1994, 264(5166), 1772-1775; Gurney et al., Ann. Neurol. 1996, 39, 147-157; Gurney, J. Neurol. Sci. 1997, 152, S67-73; Ripps et al., Proc Natl Acad Sci U.S.A. 1995, 92(3), 689-693; および Bruijn et al., Proc Natl Acad Sci U.S.A. 1997, 94(14), 7606-7611)。SOD1トランスジェニックマウスは約3ヶ月齢で後足衰弱の徴候を示し、4ヶ月で死亡する。ヒトALSに共通する特徴としては、星状細胞の増加、小神経膠細胞症、酸化的ストレス、シクロオキシゲナーゼ/プロスタグランジンのレベル増加、および疾患の進行につれて、顕著な運動ニューロンの欠損が挙げられる。
下記の臨床試験を用いて、パーキンソン病を治療する際の化合物の有効性を評価することができる。
軽度から中程度の安定した喘息のある成人被験者(非喫煙者)を登録する (例えば、Van Schoor and Pauwels, Eur Respir J 2002, 19, 997-1002を参照のこと)。無作為化、二重盲検、プラセボ対照、2期間クロスオーバー試験のデザインを採用する。スクリーニング1日目に、患者にメタコリン(methacholine)チャレンジ(<8mg/mL)をおこなう。後続の各チャレンジ前の1秒間ベースライン努力呼気量(FEV1)は、最初の来院時に得られたスクリーニングベースラインFEV1の15%以内でなければならない。スクリーニング2日目のニューロキニン(neurokinin)チャレンジ(1×10〜6mol/mL)を24〜72時間後におこなう。試験期間1は、訪問2の後の10日以内に開始する。最初に、メタコリンおよびニューロキニン-A(NKA)チャレンジをそれぞれ1日目および0日目におこなう。訪問4で、試験化合物を適切な用量で適切な期間にわたり投与する。治療期間の最後の2日間に、メタコリンおよびNKAチャレンジを繰り返す。治療期間1の後、約5週間のウォッシュアウト期間をおき、その後試験期間2(期間1と同じ)において患者を別の薬物治療またはプラセボにクロスオーバーさせる。スパイロメーターを用いて肺機能検査をおこなう。メタコリンチャレンジは、Cockcroft et al., Clin Allergy 1977, 7, 235-243に記載されるように、FEV1がその日のpostdiluent baseline FEV1の>20%低下を示すまで、次第に倍増する濃度のメタコリンを吸い込むことによりおこなう。NKAチャレンジは、Van Schoor et al., Eur Respir J 1998, 12, 17-23に記載されるように、濃度を徐々に増加させたNKAを吸い込むことによりおこなう。気道応答に及ぼす治療の効果を適切な統計学的方法により確認する。
雄モルモットを密閉したパースペックス(perspex)露出チャンバーに個別に入れて順応させてから、咳性刺激または試験化合物をエーロゾルで投与する。咳応答は、クエン酸(20%、10分)またはカプサイシン(15μM、4分)のエーロゾルに、それぞれ2L/分および3L/分の流量で曝露することにより引き出す。観察者は絶えず動物をモニタリングして、咳性刺激のエーロゾル投与の開始から15分間にわたり咳の回数を数える。次に、モルモットを無作為に割り付けて、モルモットに試験化合物または対照のいずれかを投与し、咳性刺激への曝露を繰り返して、咳の回数を記録する。
気道感染または季節性アレルギーの症状を評価前の少なくとも4週間呈しておらず、かつ正常な肺機能を示す、健康な非喫煙被験者を登録する。被験者は、ドシメーターにより制御される圧縮空気駆動ネブライザーからカプサイシン溶液(0.98μmol/L〜1,000μmol/Lの範囲)の1呼吸(single breath)を吸い込む。カプサイシン溶液の1呼吸は、チャレンジブラインドネス(challenge blindness)を高めるために生理食塩水の吸入を無作為に介在させて、5回以上の咳を誘発させる濃度に達するまで、昇順で投与する。1呼吸を1分間隔で送達する。各吸入の直後1分間にそれぞれの濃度のカプサイシンに応答して誘発された咳の数を、何も知らされていない観察者(blinded observer)に記録させる。被験者は、試験のエンドポイントが誘発された咳の数であることに気付いていない。ベースライン時のカプサイシン咳チャレンジを受けた後、被験者を二重盲検法で無作為に割り付け、適切な用量の試験化合物またはプラセボを投与し、その後咳チャレンジを繰り返す。有意な応答は、5回以上の咳を誘発させるのに必要なカプサイシン濃度の4倍またはそれ以上の増加として定義することができる。
タバコの煙に長期的に曝されたマウスを用いる動物モデルは、タバコの煙に長期的に曝されたマウスの気腫を治療する際の化合物の有効性を評価するために使用できる (例えば、Martorana et al, Am J Respir Crit Care Med, 2005, 172, 848-835; および Cavarra et al., Am J Respir Crit Care Med 2001, 164, 886-890を参照のこと)。6週齢のC57B1/6J雄マウスを用いる。急性試験では、マウスを室内空気または5本のタバコの煙に20分間曝露する。慢性試験では、マウスを室内空気または1日3本のタバコの煙に週5日間、7ヶ月にわたって曝露する。
Claims (26)
- 患者の片頭痛、線維筋痛症、筋萎縮性側索硬化症、社会恐怖症、パーキンソン病、喘息、咳、または慢性閉塞性肺疾患から選択される疾患を治療する方法であって、そのような治療が必要な患者に、治療上有効な量の式(I)、式(II)、式(III)、および式(IV)の化合物:
R1は、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択され;
R2およびR3は、それぞれ独立して、水素、アルキル、置換アルキル、アルコキシカルボニル、置換アルコキシカルボニル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、カルバモイル、置換カルバモイル、シクロアルキル、置換シクロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択されるか、またはR2およびR3は、それらが結合している炭素原子と一緒になって、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、および置換シクロヘテロアルキル環から選択される環を形成し; そして
R4は、アシル、置換アシル、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、および置換ヘテロアリールアルキルから選択される]
前記化合物のいずれかの製薬上許容される塩、前記化合物のいずれかの製薬上許容される溶媒和物、ならびに前記化合物のいずれかの製薬上許容されるN-オキシドから選択される少なくとも1種の化合物を投与することを含んでなる、上記方法。 - R1が水素である、請求項1に記載の方法。
- R2およびR3が独立して水素およびC1-6アルキルから選択される、請求項1に記載の方法。
- R2およびR3の少なくとも一方が水素以外のものである、請求項1に記載の方法。
- R3がメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、およびsec-ブチルから選択され、R2が水素である、請求項1に記載の方法。
- R4がC1-6アルキルおよびC1-6置換アルキルから選択される、請求項1に記載の方法。
- R4がメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、n-ペンチル、イソペンチル、sec-ペンチル、ネオペンチル、および1,1-ジエトキシエチルから選択される、請求項1に記載の方法。
- R1およびR2がそれぞれ水素であり、R3がC1-6アルキルであり、そしてR4がC1-6アルキルおよびC1-6置換アルキルから選択される、請求項1に記載の方法。
- R1およびR2がそれぞれ水素であり、R3がメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、およびsec-ブチルから選択され、そしてR4がメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、n-ペンチル、イソペンチル、sec-ペンチル、ネオペンチル、および1,1-ジエトキシエチルから選択される、請求項1に記載の方法。
- 前記化合物が式(III)の化合物である1-{[(α-イソブタノイルオキシエトキシ)カルボニル]アミノメチル}-1-シクロヘキサン酢酸、その製薬上許容される塩、前記化合物のいずれかの製薬上許容される溶媒和物、または前記化合物のいずれかの製薬上許容されるN-オキシドである、請求項1に記載の方法。
- 前記化合物が式(IV)の化合物である3-{[(α-イソブタノイルオキシエトキシ)カルボニル]アミノメチル}-5-メチルヘキサン酸、その製薬上許容される塩、前記化合物のいずれかの製薬上許容される溶媒和物、または前記化合物のいずれかの製薬上許容されるN-オキシドである、請求項1に記載の方法。
- 前記化合物を式(I)および式(III)から選択し、1日あたり約10mg当量〜約3600mg当量のガバペンチンの量で投与する、請求項1に記載の方法。
- 前記化合物を式(II)および式(IV)から選択し、1日あたり約10mg当量〜約1200mg当量のプレガバリンの量で投与する、請求項1に記載の方法。
- 前記化合物を経口投与する、請求項1に記載の方法。
- 前記化合物を徐放性経口剤形で投与することを含む、請求項14に記載の方法。
- ガバペンチンまたはプレガバリンの治療有効量が患者の血漿中で前記化合物の投与後少なくとも約4時間維持される、請求項15に記載の方法。
- 前記疾患が片頭痛である、請求項1に記載の方法。
- 前記治療方法が予防的に治療することを含む、請求項17に記載の方法。
- 前記疾患が線維筋痛症である、請求項1に記載の方法。
- 前記疾患が筋萎縮性側索硬化症である、請求項1に記載の方法。
- 前記疾患が社会恐怖症である、請求項1に記載の方法。
- 前記疾患がパーキンソン病である、請求項1に記載の方法。
- 前記疾患が咳である、請求項1に記載の方法。
- 前記疾患が喘息である、請求項1に記載の方法。
- 前記疾患が慢性閉塞性肺疾患である、請求項1に記載の方法。
- 前記化合物が式(III)の化合物である、請求項17〜25のいずれか1項に記載の方法。
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- 2007-12-06 AU AU2007332904A patent/AU2007332904A1/en not_active Abandoned
- 2007-12-06 EA EA200970487A patent/EA200970487A1/ru unknown
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- 2007-12-06 US US12/001,067 patent/US20080161393A1/en not_active Abandoned
- 2007-12-06 CN CN200780051141A patent/CN101652133A/zh active Pending
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MX2009006080A (es) | 2009-07-14 |
PE20081389A1 (es) | 2008-11-19 |
US20080161393A1 (en) | 2008-07-03 |
EP2101752A1 (en) | 2009-09-23 |
AU2007332904A1 (en) | 2008-06-19 |
BRPI0720252A2 (pt) | 2014-01-07 |
CA2672044A1 (en) | 2008-06-19 |
EA200970487A1 (ru) | 2009-12-30 |
US20120041061A1 (en) | 2012-02-16 |
CN101652133A (zh) | 2010-02-17 |
AR064212A1 (es) | 2009-03-18 |
WO2008073257A1 (en) | 2008-06-19 |
TW200845959A (en) | 2008-12-01 |
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