JP2019511489A - オレキシン−2受容体アンタゴニストを用いてうつ病を治療する方法 - Google Patents
オレキシン−2受容体アンタゴニストを用いてうつ病を治療する方法 Download PDFInfo
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- JP2019511489A JP2019511489A JP2018547296A JP2018547296A JP2019511489A JP 2019511489 A JP2019511489 A JP 2019511489A JP 2018547296 A JP2018547296 A JP 2018547296A JP 2018547296 A JP2018547296 A JP 2018547296A JP 2019511489 A JP2019511489 A JP 2019511489A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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Abstract
Description
本願は、参照により本明細書に組み込まれる、2016年3月10日に出願された米国特許仮出願第62/306,487号に対する優先権を主張する。
本開示は、特に、うつ病の治療方法を目的とする。
用語「うつ病」は、大うつ病性障害、持続性うつ病性障害、双極性障害(aka双極性うつ病)に関連するうつ病、季節性感情障害、精神病性うつ病、産後うつ病、月経前不快気分障害、状況うつ病、無快感症、メランコリー、中年うつ病、晩年うつ病、特定可能なストレッサーに起因するうつ病、治療抵抗性うつ病、又はこれらの組み合わせを含む。特定の実施形態では、うつ病は、大うつ病性障害である。他の実施形態では、大うつ病性障害は、憂鬱の特徴又は不安による苦悩を伴う。
上述のように、本明細書に記載される化合物は、オレキシン−2アンタゴニストであり、うつ病の治療において使用することができる。いくつかの実施形態では、化合物は、最高血漿濃度になるまでにかかる時間が、特に、約3時間未満、約2時間未満、好ましくは約1時間未満、すなわち、約45分間未満、約30分間未満、約15分間未満になるように投与される。他の実施形態では、化合物は、約4時間、典型的には約4時間未満の排出半減期を有する。例えば、本開示の特定の化合物の半減期は、約2〜約3時間、例えば、約2時間、約2.1時間、約2.2時間、約2.3時間、約2.4時間、約2.5時間、約2.6時間、約2.7時間、約2.8時間、又は約2.9時間〜約3時間である。短い半減期に鑑みて、起床時に対象中に残存している化合物の量は、典型的には、薬力学的効果に必要な閾値を下回る。例えば、本開示の化合物は、典型的には、約5mg超の用量レベルから薬力学的効果を有する。
式(I)の化合物を含む、本明細書に記載される化合物は、対象に投与するために医薬組成物として処方することができる。したがって、医薬組成物は、(a)有効量の本明細書に記載される少なくとも1つの化合物と、(b)医薬として許容できる賦形剤とを含み得る。「医薬として許容される賦形剤」は、薬理学的組成物に添加されるか、あるいは薬剤の投与を容易にするビヒクル、担体又は希釈剤として用いられかつその薬剤と相溶する、例えば、不活性な物質のような、毒性を有しないか、生物学的に許容されるか、あるいは対象に投与するうえで生物学的に適した物質を指す。賦形剤の例としては、炭酸カルシウム、リン酸カルシウム、様々な糖及びデンプンの種類、セルロース誘導体、ゼラチン、植物油、及びポリエチレングリコールが挙げられる。
本明細書に記載のとおり、本発明者らは、記載される化合物をうつ病と診断された対象に対して使用したとき、驚くべき、強い抗うつ効果を見出した。理論に束縛されるものではないが、オレキシン含有ニューロンの活性は睡眠中(典型的には夜間)無視できる程度であるので、本明細書で論じられる化合物の抗うつ有効性は驚くべきことであると考えられる。本明細書に開示されるように、本開示の化合物の睡眠前(典型的には夜間)の投与は、統計的に有意な抗うつ有効性と関連し、この有効性は睡眠項目に対する影響とは関連しない。
うつ病を治療するために本明細書に記載される1つ以上の化合物を患者に投与するためのキットも本明細書に記載される。代表的なキットは、患者に所与の頻度で投与するため、有効量の本明細書に記載される1つ以上の化合物を含む1つ以上の投薬単位を含む。
本開示は、少なくとも以下の態様を含む。
この実施例は、懸濁製剤に対する、単一用量錠剤投与後の[5(4,6−ジメチル−ピリミジン−2−イル)−ヘキサヒドロ−ピロロ[3,4−c]ピロール−2−イル]−(2−フルオロ−2−[1,2,3]トリアゾール−2−イル−フェニル)−メタノン(化合物A)の固体用量製剤の血漿薬物動態(plasma pharmacokinetic、PK)及び生物学的利用能を決定するために実施した。また、固体用量製剤の生物学的利用能の割合及び程度、並びに固体及び経口懸濁製剤の忍容性に対する半絶食状態の効果についても調べる。
エタノール/2−プロパノール混合物の代わりにエタノールを使用して再結晶化を実施したことを除いて、米国特許第8,653,263号の実施例107の方法Bに記載のとおり、[5(4,6−ジメチル−ピリミジン−2−イル)−ヘキサヒドロ−ピロロ[3,4−c]ピロール−2−イル]−(2−フルオロ−2−[1,2,3]トリアゾール−2−イル−フェニル)−メタノン(化合物A)を調製した。
・Cmaxピーク血漿濃度。
・tmaxピーク血漿濃度に到達するまでの時間。
・AUClast台形加算によって計算された、試験薬物投薬後0〜t時間の血漿濃度−時間曲線下面積(時間tは、最後の定量可能な濃度Clastの時間である)。
・AUC∞ AUClast+Clast/λzとして計算された、無限に外挿されたAUClast。
・λz ln−線形血漿濃度−時間曲線の終点の線形回帰によって決定される排出速度定数。
・t1/2 0.693/λzとして定義される消失半減期。
・CL/F Dose/AUC∞として計算される、絶対生物学的利用能について補正されていない、血管外投与後の薬物の総クリアランス。
・Vd/F絶対生物学的利用能について補正されていない、血管外投与後の見かけの分布体積。
・化合物A原液:原液希釈溶媒(10.0mL)に化合物A(1.00mg)を溶解させることによって、この溶液を調製した。
・化合物A過曲線(Overcurve)原液:2.00mLの原液希釈溶媒(2.00mL)に化合物A(2.00mg)を溶解させることによって、この溶液を調製した。
・化合物B原液:10.0mLの原液希釈溶媒(2.00mL)に化合物B(1.00mg)を溶解させることによって、この溶液を調製した。
・化合物A標準溶液1(10.0μg/mL):化合物A原液(1000μL)を原液希釈溶媒(10.0mL)と合わせた。
・化合物A標準溶液2(1.00μg/mL):化合物A原液(100μL)を原液希釈溶媒(10.0mL)と合わせた。
・化合物A標準溶液3(0.100μg/mL):化合物A原液(10.0μL)を原液希釈溶媒(10.0mL)と合わせた。
・化合物B作業溶液(Working Solution)(200mg/mL):化合物B原液(200μL)を原液希釈溶媒(100mL)と合わせた。
i.室温の血漿サンプルをホモジナイズした。
ii.約2500×g及び20℃で5分間、サンプルを遠心分離した。
iii.血漿サンプル(50.0μL)を、1.2mL丸底ウェル収集プレートにピペットで入れた。
iv.原液希釈溶媒(50.0μL)をブランクに添加し、内部標準作業溶液を全ての他のチューブに添加した。次いで、チューブを10秒間ボルテックスした。
v.アセトニトリル(100μL)を各チューブに添加し、そのチューブを10秒間再度ボルテックスで混合した。
vi.アセトニトリル(250μL)を各チューブに更に添加し、そのチューブを60秒間再度ボルテックスで混合した。
vii.約2500×g及び20℃で5分間、サンプルを遠心分離した。
viii.リキデータ(liquidator)を使用して、上清(50.0μL)を1.2mL丸底ウェル収集プレートに移した。
ix.水中ギ酸(0.1%;400μL)を各チューブに添加し、そのチューブを10秒間ボルテックスで混合した。
ヒプロメロース(5mg/mL)溶液で粉末(100mg化合物A)を再構成して、化合物Aの経口5mg/mL経口懸濁液を提供することによって、化合物Aを含有する懸濁液を調製した。再構成に使用したヒプロメロースは、注射用滅菌水中0.5%ヒプロメロース溶液である。
(i)化合物Aを含有する粉末をバイアルに添加した。
(ii)懸濁液の所望の濃度を達成するために、適切な量の0.5%HPMC溶液をバイアルに添加した。
(iii)バイアルに清潔な攪拌棒を添加した。
(iv)原体を懸濁させる必要があったので、スピンバーの入ったバイアルを磁気撹拌板上に載置し、速度を調整して液体中に緩やかに渦を発生させた。緩やかな渦ができたら、2500RPM(約2400〜約2600)で急速にボルテックスするために攪拌棒の速度を増大させた。
(v)最低約24〜約36時間、組成物を混合した。
(vi)混合後、懸濁液の使用準備が整ったので、投与のために必要な体積を引き出した。
1.1000rpmで07L039R03125ふるいを使用して、ステアリン酸マグネシウムを除く全ての材料をQuadro Comilに通した。ふるいに材料を添加する順序は以下のとおりであった:
(i)ラクトース一水和物の約1/2
(ii)化合物A
(iii)コロイド状二酸化ケイ素
(iv)クロスポビドン
(v)微結晶セルロース
(vi)ラクトース一水和物の約半分
2.混合物を20rpmで20分間ブレンドした。
3.#40ふるいを通してステアリン酸マグネシウムをふるった。
4.工程3の混合物を20rpmで5分間ブレンドした。
「D」型の7.0mmの丸底の浅い凹部を有するパンチ及び適切なダイを備えるロータリープレスを使用して、錠剤を圧縮した。インプロセスパラメータは、表6に記載のとおりである。
18歳〜55歳の男性対象18人を試験した。対象は、14日間以内若しくは薬物の半減期の5倍未満の期間(どちらか長い方)強力なシトクロムP450(CYP)3A及びCYP2C19阻害剤を服用しなかったか、又は期間1の1日目の試験薬物投与前30日間以内の強力なCYP3A若しくはCYP2C19誘導剤を除外した。
・処理A:化合物Aの20mg経口懸濁製剤(絶食状態)
・処理B:化合物Aの20mg固体製剤(絶食状態)
・処理C:化合物Aの20mg固体製剤(半絶食状態)
自然対数変換されたCmax及びAUCに混合効果モデルを適用した。このモデルは、固定効果として順序、期間、処理を含み、変量効果として対象を含んでいた。各パラメータについて、比較は以下を含んでいた:
・固体投薬製剤(絶食)対経口懸濁製剤(絶食)
・固体投薬製剤(絶食)対固体投薬製剤(半絶食)
この実施例は、多施設二重盲検ジフェンヒドラミン及びプラセボ対照試験として実施した。18歳〜64歳のMDDと診断された男性及び女性が登録された。スクリーニング時に、対象はIDS−C30において≧30の合計スコアを有しており、これは中等度〜重篤なうつ病に対応する。
化合物Aは、オレキシン−2受容体の経口的に活性のある選択的アンタゴニストであることが見出された。20mgの経口投与後、化合物Aは、最高血漿濃度になるまでにかかる時間がより短く(Tmax<1時間)、短い半減期を特徴としていた(2〜3時間)。化合物Aの日中投与は健常対象において傾眠を誘発したが、夜間投与は、不眠障害(insomnia disorder、ID)の対象において持続性睡眠までの待ち時間(LPS)を短縮し、合計睡眠時間(TST)を延長した。LPS及びTSTに対する化合物Aの効果の大きさは、ベースラインにおける不眠のレベルに直接関連する。図12〜15を参照のこと。
試験中に得られた17項目のスコアを合計することによって、HDRS17合計スコアを計算した。HDRS17合計スコアは0〜52の範囲であり、より高いスコアがより重篤なうつ病を示す。睡眠に対する試験薬の推定される効果を補正するために、睡眠に関連する項目をHDRS17から除去して、(睡眠項目)調整HDRSを計算した。したがって、3つの不眠症に関する質問を除く項目のスコアを合計することによって、調整されたHDRS17合計スコアを計算した(4−初期不眠症、5−中期不眠症、及び6−後期不眠症)。HDRS17調整合計スコアは、0〜46の範囲である。HDRS17(HAM−D6)から6項目のサブスケールを分析し、中核うつ病症状に情報を提供した。このサブスケールは、治療応答に対して感受性である。6項目は、抑うつ気分、罪悪感、労働及び関心、精神運動遅延、精神的不安、並びに全身症状(疲労感及び疼痛)を含んでいた。
睡眠ポリグラフ(PSG)由来のパラメータに対する試験薬の効果を、1/2及び10/11日目に終夜評価した。更に、5/6日目に終夜、強制的に起こすまで及び起こした後のPSGを記録した。2回スクリーニングPSG記録を行い、スクリーニング1及び2で記録された平均値としてベースライン値を計算した。
TSTは、レム(REM)睡眠及びノンレム睡眠に費やされた合計分数として定義される。プラセボと比較して、化合物A及びジフェンヒドラミンはいずれも1/2日目に終夜TSTを増加させた。10/11日目におけるプラセボ処理対象におけるTSTの増加に起因して、化合物A及びジフェンヒドラミンの相対効果はそれほど顕著ではなかった。表9を参照されたい。試験集団全体が不眠障害の基準(TST<360分間)を満たした訳ではなかったが、個々の対象はわずか263分間しかベースラインTST値を有していなかった。したがって、不眠障害の存在に関して集団は混在していた。
LPSは、消灯から10分間の連続睡眠までの経過時間(分)と定義される。プラセボと比較して、化合物A及びジフェンヒドラミンはいずれも1/2日目に終夜LPSが穏やかに低下した。10/11日目における終夜のプラセボ処理対象におけるLPSの減少に起因して、化合物A及びジフェンヒドラミンの相対効果はそれほど顕著ではなかった。表10を参照されたい。全体として、試験集団は、延長された(>20分間)LPSを特徴としていた。TSTと同様に、LPS値がわずか4.5分間であるベースラインにおいて不眠障害の存在に関して集団は混在していた。
これら結果は、プラセボ及びジフェンヒドラミンと比較して、化合物Aの抗うつ効果がより大きく、臨床的に関連があることを示す。驚くべきことに、化合物Aの効果は、うつ病の中核症状に対する効果と大きく関連しており、全体的に、睡眠関連項目に対する効果とは関連していなかった。抗うつ効果は、処理中断後少なくとも14日間維持された。重要なことに、11日目(最初の評価)には既に改善が観察され、処理中断時に維持されていた。
この実施例は、化合物Aを補助療法で使用することができることを示すために実施した。具体的には、(i)単剤療法として、及び(ii)公知の抗うつ剤と組み合わせて、MDDと診断された対象に化合物Aを投与し、HDRS17及びHAM−D6尺度を使用して、対象のうつ病の症状を評価した。
Claims (24)
- うつ病に罹患しているか又は該うつ病と診断された対象を治療する方法であって、このような治療を必要とする対象に、有効量の、式(I)の化合物:
R1は、C1〜4アルキルであり、
R2は、C1〜4アルキルであり、
R3は、H又はハロゲンであり、
R4は、H又はC1〜4アルコキシである)、
又はその医薬として許容される塩若しくは水和物を投与することを含み、
前記化合物が、睡眠前に投与される、方法。 - 前記対象が、不眠障害に罹患しておらず、該不眠障害と診断されてもいない、請求項1に記載の方法。
- R3がハロゲンである、請求項1に記載の方法。
- R3がフッ素である、請求項3に記載の方法。
- R4がHである、請求項1に記載の方法。
- R4がC1〜4アルコキシである、請求項1に記載の方法。
- R4がメトキシである、請求項6に記載の方法。
- R3がHである、請求項1に記載の方法。
- R1がCH3である、請求項1に記載の方法。
- R2がCH3である、請求項1に記載の方法。
- 前記化合物が、5−(4,6−ジメチル−ピリミジン−2−イル)−ヘキサヒドロ−ピロロ[3,4−c]ピロール−2−イル]−(2−フルオロ−6−[1,2,3]トリアゾール−2−イル−フェニル)−メタノン又はその医薬として許容される塩である、請求項1に記載の方法。
- 前記化合物が、5−(4,6−ジメチル−ピリミジン−2−イル)−ヘキサヒドロ−ピロロ[3,4−c]ピロール−2−イル]−(2−フルオロ−6−[1,2,3]トリアゾール−2−イル−フェニル)−メタノンである、請求項1に記載の方法。
- 前記化合物が、5−(4,6−ジメチル−ピリミジン−2−イル)−ヘキサヒドロ−ピロロ[3,4−c]ピロール−2−イル]−(2−フルオロ−6−[1,2,3]トリアゾール−2−イル−フェニル)−メタノン塩酸塩である、請求項1に記載の方法。
- 前記化合物が、(5−(4,6−ジメチルピリミジン−2−イル)ヘキサヒドロピロロ[3,4−c]ピロール−2(1H)−イル)(4−メトキシ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル)メタノン又はその医薬として許容される塩である、請求項1に記載の方法。
- 前記化合物が、(5−(4,6−ジメチルピリミジン−2−イル)ヘキサヒドロピロロ[3,4−c]ピロール−2(1H)−イル)(4−メトキシ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル)メタノンである、請求項1に記載の方法。
- 前記化合物が夜間に投与される、請求項1に記載の方法。
- 前記化合物が毎日投与される、請求項1に記載の方法。
- 前記化合物が経口投与される、請求項1に記載の方法。
- 前記有効量が、約10〜約40mgである、請求項1に記載の方法。
- 前記うつ病が、大うつ病性障害、双極性疾患に関連するうつ病、又は治療抵抗性うつ病を含む、請求項1に記載の方法。
- 前記うつ病が大うつ病性障害である、請求項20に記載の方法。
- 前記うつ病が治療抵抗性うつ病である、請求項20に記載の方法。
- 第2の抗うつ剤を投与することを更に含む、請求項1に記載の方法。
- 前記第2の抗うつ剤が、選択的セロトニン再取込み阻害剤、セロトニン及びノルアドレナリン再取込み阻害剤、又はこれらの組み合わせである、請求項23に記載の方法。
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