JP2019048898A - インフルエンザウイルスの複製の阻害剤 - Google Patents
インフルエンザウイルスの複製の阻害剤 Download PDFInfo
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- JP2019048898A JP2019048898A JP2019000201A JP2019000201A JP2019048898A JP 2019048898 A JP2019048898 A JP 2019048898A JP 2019000201 A JP2019000201 A JP 2019000201A JP 2019000201 A JP2019000201 A JP 2019000201A JP 2019048898 A JP2019048898 A JP 2019048898A
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- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 238000001107 thermogravimetry coupled to mass spectrometry Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Description
本PCT出願は、2013年11月13日に出願された米国仮出願第61/903,572号の利益を主張する。この文書は本明細書においてその全体が参照として援用される。
本発明は、インフルエンザウイルスの複製を阻害するため、患者におけるインフルエンザ感染を処置するためまたはその重症度を低下させるため、および患者におけるインフルエンザ感染を予防的に防ぐためまたはその発生率を低下させるために有用な化合物および固体の形態の化合物に関する。
インフルエンザは、季節的流行として世界中に広がり、それによって、毎年数十万人、世界的に流行した年には数百万人が死亡する。例えば、インフルエンザの世界的流行は、20世紀に3度発生し、それにより数千万人が死亡し、これらの世界的流行の各々は、そのウイルスの新しい株がヒトに出現したことが原因だった。これらの新しい株は、既存のインフルエンザウイルスが他の動物種からヒトに伝播することに起因することが多い。
本発明は、概して、多形体(polymorphic forms)の化合物(1)またはその薬学的に許容され得る塩、その薬学的に許容され得る製剤、そのような多形体の化合物(1)を調製する方法、ならびにインフルエンザウイルスの複製を阻害するため、インフルエンザウイルスの量を減少させるためおよびインフルエンザを処置するためのそのような多形体の使用に関する。
一実施形態において、例えば、以下の項目が提供される。
(項目1)
多形体の化合物(1)またはその薬学的に許容され得る塩であって、ここで、化合物(1)は、以下の構造式:
によって表され、該多形体は、
A形の化合物(1)・1/2H2OのHCl塩、
F形の化合物(1)・3H2OのHCl塩、
D形の化合物(1)のHCl塩、
A形の化合物(1)、および
A形の化合物(1)のトシレート塩
からなる群より選択される、多形体の化合物(1)またはその薬学的に許容され得る塩。
(項目2)
前記多形体が、A形の化合物(1)・1/2H2OのHCl塩である、項目1に記載の多形体。
(項目3)
A形の化合物(1)・1/2H2OのHCl塩が、粉末X線回折パターンにおいて、10.5±0.2、5.2±0.2、7.4±0.2および18.9±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークを特徴とする、項目2に記載の多形体。
(項目4)
A形の化合物(1)・1/2H2OのHCl塩が、粉末X線回折パターンにおいて、25.2±0.2、16.5±0.2、18.1±0.2および23.0±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークをさらに特徴とする、項目3に記載の多形体。
(項目5)
A形の化合物(1)・1/2H2OのHCl塩が、C13 SSNMRスペクトルにおいて、29.2±0.3ppm、107.0±0.3ppm、114.0±0.3ppmおよび150.7±0.3ppmに対応する1つまたはそれを超えるピークを特徴とする、項目2〜4のいずれかに記載の多形体。
(項目6)
A形の化合物(1)・1/2H2OのHCl塩が、C13 SSNMRスペクトルにおいて、22.1±0.3ppm、24.6±0.3ppm、47.7±0.3ppmおよび54.8±0.3ppmに対応する1つまたはそれを超えるピークをさらに特徴とする、項目5に記載の多形体。
(項目7)
前記多形体が、F形の化合物(1)・3H2OのHCl塩である、項目1に記載の多形体。
(項目8)
F形の化合物(1)・3H2OのHCl塩が、粉末X線回折パターンにおいて、7.1±0.2、11.9±0.2、19.2±0.2および12.4±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークを特徴とする、項目7に記載の多形体。
(項目9)
F形の化合物(1)・3H2OのHCl塩が、粉末X線回折パターンにおいて、16.4±0.2、21.8±0.2および23.9±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークをさらに特徴とする、項目8に記載の多形体。
(項目10)
F形の化合物(1)・3H2OのHCl塩が、C13 SSNMRスペクトルにおいて、20.7±0.3ppm、27.4±0.3ppm、104.8±0.3ppm、142.5±0.3ppmおよび178.6±0.3ppmに対応する1つまたはそれを超えるピークを特徴とする、項目7〜9のいずれかに記載の多形体。
(項目11)
F形の化合物(1)・3H2OのHCl塩が、C13 SSNMRスペクトルにおいて、154.3±0.3ppm、20.3±0.3ppm、132.3±0.3ppmおよび21.1±0.3ppmに対応する1つまたはそれを超えるピークをさらに特徴とする、項目10に記載の多形体。
(項目12)
前記多形体が、D形の化合物(1)のHCl塩である、項目1に記載の多形体。
(項目13)
D形の化合物(1)のHCl塩が、粉末X線回折パターンにおいて、5.8±0.2、19.5±0.2および17.1±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークを特徴とする、項目12に記載の多形体。
(項目14)
D形の化合物(1)のHCl塩が、粉末X線回折パターンにおいて、5.3±0.2、10.5±0.2および15.9±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークをさらに特徴とする、項目13に記載の多形体。
(項目15)
D形の化合物(1)のHCl塩が、C13 SSNMRスペクトルにおいて、29.4±0.3ppm、53.4±0.3ppm、113.3±0.3ppm、135.4±0.3ppmおよび177.8±0.3ppmに対応する1つまたはそれを超えるピークを特徴とする、項目12〜14のいずれかに記載の多形体。
(項目16)
D形の化合物(1)のHCl塩が、C13 SSNMRスペクトルにおいて、22.9±0.3ppm、23.9±0.3ppm、26.0±0.3ppmおよび31.6±0.3ppmに対応する1つまたはそれを超えるピークをさらに特徴とする、項目15に記載の多形体。
(項目17)
前記多形体が、A形の化合物(1)である、項目1に記載の多形体。
(項目18)
A形の化合物(1)が、粉末X線回折パターンにおいて、15.5±0.2、18.9±0.2および22.0±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークを特徴とする、項目17に記載の多形体。
(項目19)
A形の化合物(1)が、粉末X線回折パターンにおいて、11.8±0.2、16.9±0.2、25.5±0.2および9.1±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークをさらに特徴とする、項目18に記載の多形体。
(項目20)
A形の化合物(1)が、C13 SSNMRスペクトルにおいて、21.0±0.3ppm、28.5±0.3ppm、50.4±0.3ppm、120.8±0.3ppm、138.5±0.3ppmおよび176.2±0.3ppmに対応する1つまたはそれを超えるピークを特徴とする、項目17〜19のいずれかに記載の多形体。
(項目21)
A形の化合物(1)が、C13 SSNMRスペクトルにおいて、30.1±0.3ppm、25.9±0.3ppm、22.8±0.3ppmおよび25.0±0.3ppmに対応する1つまたはそれを超えるピークをさらに特徴とする、項目20に記載の多形体。
(項目22)
前記多形体が、A形の化合物(1)のトシレート塩である、項目1に記載の多形体。
(項目23)
A形の化合物(1)のトシレート塩が、粉末X線回折パターンにおいて、7.2±0.2、9.3±0.2、13.7±0.2、14.3±0.2、14.7±0.2、16.9±0.2、18.7±0.2、26.3±0.2および26.9±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークを特徴とする、項目22に記載の多形体。
(項目24)
A形の化合物(1)のトシレート塩が、粉末X線回折パターンにおいて、6.0±0.2、28.0±0.2および27.5±0.2度の単位で計測された2−シータ値に対応する1つまたはそれを超えるピークをさらに特徴とする、項目23に記載の多形体。
(項目25)
項目1に記載の多形体および少なくとも1つの薬学的に許容され得るキャリアまたは賦形剤を含む、薬学的組成物。
(項目26)
前記多形体が、A形の化合物(1)・1/2H2OのHCl塩である、項目25に記載の薬学的組成物。
(項目27)
前記多形体が、F形の化合物(1)・3H2OのHCl塩である、項目25に記載の薬学的組成物。
(項目28)
前記多形体が、D形の化合物(1)のHCl塩である、項目25に記載の薬学的組成物。(項目29)
前記多形体が、A形の化合物(1)である、項目25に記載の薬学的組成物。
(項目30)
前記多形体が、A形の化合物(1)のトシレート塩である、項目25に記載の薬学的組成物。
(項目31)
生物学的インビトロサンプルまたは被験体におけるインフルエンザウイルスの量を減少させる方法であって、該方法は、該サンプルに有効量の項目1〜24のいずれか1項に記載の多形体の化合物(1)を投与する工程を含む、方法。
(項目32)
生物学的インビトロサンプルまたは被験体におけるインフルエンザウイルスの複製を阻害する方法であって、該方法は、該サンプルに有効量の項目1〜24のいずれか1項に記載の多形体の化合物(1)を投与する工程を含む、方法。
(項目33)
被験体におけるインフルエンザを処置する方法であって、該方法は、該被験体に治療有効量の項目1〜24のいずれか1項に記載の多形体の化合物(1)を投与する工程を含む、方法。
(項目34)
1つまたはそれを超えるさらなる治療薬を前記被験体に共投与する工程をさらに含む、項目31〜33のいずれか1項に記載の方法。
(項目35)
前記さらなる治療薬が、抗ウイルス薬を含む、項目34に記載の方法。
(項目36)
前記抗ウイルス薬が、ノイラミニダーゼ阻害剤である、項目35に記載の方法。
(項目37)
前記ノイラミニダーゼ阻害剤が、オセルタミビルまたはザナミビルである、項目36に記載の方法。
(項目38)
前記抗ウイルス薬が、ポリメラーゼ阻害剤である、項目35に記載の方法。
(項目39)
前記ポリメラーゼ阻害剤が、ファビピラビルである、項目38に記載の方法。
(項目40)
前記インフルエンザウイルスが、インフルエンザAウイルスである、項目31〜39のいずれか1項に記載の方法。
(項目41)
A形の化合物(1)・1/2H2OのHCl塩を調製する方法であって、ここで、化合物(1)は、以下の構造式:
によって表され、該方法は、水および1つまたはそれを超える有機溶媒を含む溶媒系において、HClを化合物(1)と混合する工程を含み、ここで、該溶媒系は、0.05〜0.85の水分活性を有する、方法。
(項目42)
前記溶媒系が、クロロベンゼン、シクロヘキサン、1,2−ジクロロエテン、ジクロロメタン、1,2−ジメトキシエタン、N,N−ジメチルアセトアミド、N,N−ジメチルホルムアミド、1,4−ジオキサン、2−エトキシエタノール、ホルムアミド、ヘキサン、2−メトキシエタノール、メチルブチルケトン、メチルシクロヘキサン、N−メチルピロリドン、ニトロメタン、ピリジン、スルホラン、テトラヒドロフラン(THF)、テトラリン、トルエン、1,1,2−トリクロロエテンおよびキシレン、酢酸、アセトン、アニソール、1−ブタノール、2−ブタノール、酢酸ブチル、tert−ブチルメチルエーテル、クメン、ヘプタン、酢酸イソブチル、酢酸イソプロピル、酢酸メチル、3−メチル−1−ブタノール、メチルエチルケトン、メチルイソブチルケトン、2−メチル−1−プロパノール、酢酸エチル、エチルエーテル、ギ酸エチル、ペンタン、1−ペンタノール、1−プロパノール、2−プロパノール、酢酸プロピルまたはそれらの任意の組み合わせから選択される1つまたはそれを超える有機溶媒を含む、項目41に記載の方法。
(項目43)
前記溶媒系が、クロロベンゼン、シクロヘキサン、1,2−ジクロロエタン、ジクロロメタン、1,2−ジメトキシエタン、ホルムアミド、ヘキサン、2−メトキシエタノール、メチルブチルケトン、メチルシクロヘキサン、ニトロメタン、テトラリン、キシレン、トルエン、1,1,2−トリクロロエタン、アセトン、アニソール、1−ブタノール、2−ブタノール、酢酸ブチル、tert−ブチルメチルエーテル、クメン、エタノール、酢酸エチル、エチルエーテル、ギ酸エチル、ヘプタン、酢酸イソブチル、酢酸イソプロピル、酢酸メチル、3−メチル−1−ブタノール、メチルエチルケトン、2−メチル−1−プロパノール、ペンタン、1−プロパノール、1−ペンタノール、2−プロパノール、酢酸プロピル、テトラヒドロフラン、メチルテトラヒドロフランまたはそれらの任意の組み合わせから選択される1つまたはそれを超える有機溶媒を含む、項目42に記載の方法。
(項目44)
溶媒系が、2−エトキシエタノール、エチレングリコール、メタノール、2−メトキシエタノール、1−ブタノール、2−ブタノール、3−メチル−1−ブタノール、2−メチル−1−プロパノール、エタノール、1−ペンタノール、1−プロパノール、2−プロパノール、メチルブチルケトン、アセトン、メチルエチルケトン、メチルイソブチルケトン、酢酸ブチル、酢酸イソブチル、酢酸イソプロピル、酢酸メチル、酢酸エチル、酢酸プロピル、ピリジン、トルエン、キシレンまたはそれらの任意の組み合わせから選択される1つまたはそれを超える有機溶媒を含む、項目42に記載の方法。
(項目45)
溶媒系が、アセトン、n−プロパノール、イソプロパノール、酢酸イソブチル、酢酸またはそれらの任意の組み合わせから選択される1つまたはそれを超える有機溶媒を含む、項目42に記載の方法。
(項目46)
前記溶媒系が、アセトンまたはイソプロパノールから選択される1つまたはそれを超える有機溶媒を含む、項目42に記載の方法。
(項目47)
前記溶媒系が、0.4〜0.6の水分活性値を有する、項目41〜46のいずれか1項に記載の方法。
(項目48)
前記混合が、5℃〜75℃の範囲内の温度において行われる、項目41〜47のいずれか1項に記載の方法。
(項目49)
前記HClが、水溶液の重量基準で30wt%〜40wt%のHClを有する水溶液として投入される、項目41〜48のいずれか1項に記載の方法。
(項目50)
F形の化合物(1)・3H2OのHCl塩を調製する方法であって、ここで、化合物1は、以下の構造式:
によって表され、該方法は、
(a)水を含む溶媒系において、HClおよび化合物(1)を混合する工程であって、ここで、該溶媒系は、0.9に等しいかまたはそれを超える水分活性を有する、工程;または
(b)水を含む溶媒系において、A形の化合物(1)・1/2H2OのHCl塩を撹拌する工程であって、ここで、該溶媒系は、0.9に等しいかまたはそれを超える水分活性を有する、工程
を含む、方法。
(項目51)
前記溶媒系が、クロロベンゼン、シクロヘキサン、1,2−ジクロロエテン、ジクロロメタン、1,2−ジメトキシエタン、N,N−ジメチルアセトアミド、N,N−ジメチルホルムアミド、1,4−ジオキサン、2−エトキシエタノール、ホルムアミド、ヘキサン、2−メトキシエタノール、メチルブチルケトン、メチルシクロヘキサン、N−メチルピロリドン、ニトロメタン、ピリジン、スルホラン、テトラヒドロフラン(THF)、テトラリン、トルエン、1,1,2−トリクロロエテンおよびキシレン、酢酸、アセトン、アニソール、1−ブタノール、2−ブタノール、酢酸ブチル、tert−ブチルメチルエーテル、クメン、ヘプタン、酢酸イソブチル、酢酸イソプロピル、酢酸メチル、3−メチル−1−ブタノール、メチルエチルケトン、メチルイソブチルケトン、2−メチル−1−プロパノール、酢酸エチル、エチルエーテル、ギ酸エチル、ペンタン、1−ペンタノール、1−プロパノール、2−プロパノール、酢酸プロピルまたはそれらの任意の組み合わせから選択される1つまたはそれを超える有機溶媒をさらに含む、項目50に記載の方法。
(項目52)
前記溶媒系が、クロロベンゼン、シクロヘキサン、1,2−ジクロロエタン、ジクロロメタン、1,2−ジメトキシエタン、ホルムアミド、ヘキサン、2−メトキシエタノール、メチルブチルケトン、メチルシクロヘキサン、ニトロメタン、テトラリン、キシレン、トルエン、1,1,2−トリクロロエタン、アセトン、アニソール、1−ブタノール、2−ブタノール、酢酸ブチル、tert−ブチルメチルエーテル、クメン、エタノール、酢酸エチル、エチルエーテル、ギ酸エチル、ヘプタン、酢酸イソブチル、酢酸イソプロピル、酢酸メチル、3−メチル−1−ブタノール、メチルエチルケトン、2−メチル−1−プロパノール、ペンタン、1−プロパノール、1−ペンタノール、2−プロパノール、酢酸プロピル、テトラヒドロフランまたはメチルテトラヒドロフランから選択される1つまたはそれを超える有機溶媒をさらに含む、項目51に記載の方法。
(項目53)
前記溶媒系が、2−エトキシエタノール、エチレングリコール、メタノール、2−メトキシエタノール、1−ブタノール、2−ブタノール、3−メチル−1−ブタノール、2−メチル−1−プロパノール、エタノール、1−ペンタノール、1−プロパノール、2−プロパノール、メチルブチルケトン、アセトン、メチルエチルケトン、メチルイソブチルケトン、酢酸ブチル、酢酸イソブチル、酢酸イソプロピル、酢酸メチル、酢酸エチル、酢酸プロピル、ピリジン、トルエン、キシレンまたはそれらの任意の組み合わせから選択される1つまたはそれを超える有機溶媒をさらに含む、項目51に記載の方法。
(項目54)
前記溶媒系が、イソプロパノール、アセトンまたはそれらの任意の組み合わせから選択される1つまたはそれを超える有機溶媒をさらに含む、項目51に記載の方法。
(項目55)
D形の化合物(1)のHCl塩を調製する方法であって、ここで、化合物(1)は、以下の構造式:
によって表され、該方法は、
A形の化合物(1)・1/2H2OのHCl塩を脱水する工程
を含む、方法。
(項目56)
A形の化合物(1)を調製する方法であって、ここで、化合物(1)は、以下の構造式:
(a)水およびエタノールを含む溶媒系において、非晶質の化合物(1)または化合物(1)の溶媒和物を撹拌する工程
を含む、方法。
(項目57)
前記撹拌工程が、18℃〜90℃の範囲内の温度において行われる、項目56に記載の方法。
(項目58)
前記溶媒系が、該溶媒系の重量基準で5wt%〜15wt%の水を含む、項目56または57のいずれかに記載の方法。
(項目59)
(b)ニトロメタン中で非晶形の化合物(1)を撹拌することにより、A形の化合物(1)の種結晶を形成する工程;および
(c)該A形の化合物(1)の種結晶を前記混合工程(a)で得られた混合物に加える工程
をさらに含む、項目56〜58のいずれか1項に記載の方法。
(項目60)
前記撹拌工程(a)が、前記溶媒系の還流温度において行われる、項目56〜59のいずれか1項に記載の方法。
(項目61)
(b)ニトロメタン中で前記非晶形の化合物(1)を撹拌することにより、A形の化合物(1)の種結晶を形成する工程;および
(c)前記混合工程(a)で得られた混合物を18℃〜60℃の範囲内の温度に冷却する工程;および
(d)該A形の化合物(1)の種結晶を工程(c)で得られた混合物に加える工程
をさらに含む、項目56〜58のいずれかに記載の方法。
(項目62)
水の添加後に、結果として生じる溶媒系が15wt%〜25wt%の水を含むことになるのに十分な量の水を、A形の化合物(1)の種結晶を加える前に、前記還流工程を経て得られた混合物に加える工程をさらに含む、項目61に記載の方法。
(項目63)
水の添加後に、結果として生じる溶媒系が35wt%〜45wt%の水を含むことになるのに十分な量の水を、A形の化合物(1)の種結晶を含む混合物に加える工程をさらに含む、項目61に記載の方法。
(項目64)
水の添加後に、A形の化合物(1)の種結晶を含む混合物を0℃〜10℃の温度に冷却する工程をさらに含む、項目61に記載の方法。
(項目65)
A形の化合物(1)のトシレート塩を調製する方法であって、ここで、化合物(1)は、以下の構造式:
によって表され、該方法は、非晶質の化合物(1)または化合物(1)の溶媒和物、p−トルエンスルホン酸、およびアセトニトリルを含む溶媒系の混合物を撹拌する工程を含む、方法。
(項目66)
化合物(1)の2−メチルテトラヒドロフラン溶媒和物であって、ここで、化合物(1)は、以下の構造式:
によって表される、化合物(1)の2−メチルテトラヒドロフラン溶媒和物。
(項目67)
項目1〜24のいずれか1項に記載の多形体の化合物(1)またはその薬学的に許容され得る塩を100mg〜1,600mgの投与量で被験体に投与する工程を含む投与レジメンであって、ここで、該投与量は、1日あたり1回、2回または3回投与される、投与レジメン。
(項目68)
前記投与量が、300mg〜1,600mgである、項目67に記載の投与レジメン。
(項目69)
前記投与量が、600mg〜1,200mgである、項目68に記載の投与レジメン。
(項目70)
前記投与量が、1日あたり1回投与される、項目69に記載の投与レジメン。
(項目71)
前記投与量が、600mgまたは800mgである、項目70に記載の投与レジメン。
(項目72)
前記投与量が、300mg〜900mgである、項目68に記載の投与レジメン。
(項目73)
前記投与量が、1日あたり2回投与される、項目72に記載の投与レジメン。
(項目74)
前記投与量が、400mgまたは600mgである、項目68に記載の投与レジメン。
(項目75)
前記多形体の化合物(1)またはその薬学的に許容され得る塩が、1日間からインフルエンザシーズン全体までの処置期間にわたって投与される、項目67〜74のいずれか1項に記載の投与レジメン。
(項目76)
前記処置期間が、3日間〜14日間である、項目75に記載の投与レジメン。
(項目77)
前記処置期間が、3日間、4日間または5日間である、項目76に記載の投与レジメン。(項目78)
600mg〜1,600mgの負荷投与量が、1日目に前記被験体に投与され、400mg〜1,200mgの投与量が、前記処置期間の残りの期間にわたって該被験体に投与される、項目67〜77のいずれか1項に記載の投与レジメン。
(項目79)
900mg〜1,600mgの負荷投与量が、1日目に前記被験体に投与され、400mg〜1,200mgの投与量が、前記処置期間の残りの期間にわたって該被験体に投与される、項目78に記載の投与レジメン。
(項目80)
900mgまたは1,200mgの負荷投与量が、1日目に前記被験体に投与され、600mg〜800mgの投与量が、前記処置期間の残りの期間にわたって該被験体に投与される、項目79に記載の投与レジメン。
(項目81)
900mgの負荷投与量が、1日目に前記被験体に投与され、600mgの投与量が、前記処置期間の残りの期間にわたって該被験体に1日1回投与される、項目80に記載の投与レジメン。
(項目82)
1,200mgの負荷投与量が、1日目に前記被験体に投与され、600mgの投与量が、前記処置期間の残りの期間にわたって該被験体に1日1回投与される、項目80に記載の投与レジメン。
I.固体形態
SSNMRスペクトルにおいて、29.4、53.4、113.3、135.4、177.8(±0.3ppm)にピークを有すると特徴づけられる。なおも別の具体的な実施形態において、D形の化合物(1)のHCl塩は、C13 SSNMRスペクトルにおいて、22.9、23.9、26.0および31.6(±0.3ppm)に対応する1つまたはそれを超えるピークをさらに特徴とする。なおも別の具体的な実施形態において、D形の化合物(1)のHCl塩は、表8に列挙されるC13 SSNMRピークを有すると特徴づけられる。なおも別の具体的な実施形態において、D形の化合物(1)のHCl塩は、図6に示されるものと実質的に同じC13 SSNMRスペクトルを有すると特徴づけられる。
Muischnek,H.,Arch.Exp.Pathol Pharmacol.114:313−326(1926))および半有効方程式(median−effect equation)(Chou,T.C.and Talalay,P.,Adv.Enzyme Regul.22:27−55(1984))が挙げられる。上で言及した各方程式は、実験データに利用することにより、対応するグラフを作成することができ、薬物の併用の効果の評価に役立つ。上で言及した方程式に関連する対応するグラフは、それぞれ、濃度−効果曲線、アイソボログラム曲線および併用指数曲線である。
NMR (CDCl3, 300 MHz): δ 8.34−8.33 (m, 1H); 8.07 (d, J= 8.2Hz, 2H); 7.85 (s, 1H); 7.52−7.49 (m, 1H); 7.32−7.28 (m, 2H); 2.40 (s, 3H) ppm.
(s, 3H); 1.38 (s, 12H) ppm.
δ 11.45 (br. s, 1H), 6.41 (t, J = 7.2 Hz, 1H), 6.25 (t, J = 7.2 Hz, 1H), 4.18 (m, 2H), 3.27 (m, 1H), 3.03 (m, 1H), 2.95 (m, 1H), 2.77 (m, 1H), 1.68 (m, 1H), 1.49 (m, 1H), 1.25 (t, J = 7.2Hz), 1.12 (m, 1H).
cat#H2198)を、3時間にわたって滴下漏斗によってゆっくり加えた。添加後、加熱を止め、得られたスラリーを、一晩、周囲温度まで冷却しながら機械的に撹拌した。次いで、得られた混合物を濾過し、回収された固体を、n−ヘプタン中の10%トルエンで洗浄した(2×210ml;各洗液は、21ml(16g)のトルエンおよび189ml(132g)のn−ヘプタンを混合することによって調製された)。ほんの少しの濾液しか観察されなくなるまで、真空を付加した。次いで、固体を、窒素を流しながら真空下、50℃でさらに一定重量になるまで(3.5時間)乾燥することにより、64.7g(90%)の化合物13aを得た。1H NMRによるその固体のサンプルの解析は、その材料が構造と一致することを示し、LC解析は、提供されるLC方法を用いて、99.8%の純度を示した。
SSNMRピークを、それぞれ表5および表6に要約する。
Children’s Research Hospital,Memphis,TN)から入手した。ウイルスストックをMDCK細胞において増幅した後、BALB/cマウスにおいて致死性について滴定した。インフルエンザA/Victoria/3/75(H3N2)ウイルスを、American Type Culture Collection(Manassas,VA)から入手した。そのウイルスを、マウスに適合させるためにマウスにおいて7回継代接種した後、MDCK細胞において1回継代した。適切な致死性のチャレンジ用量を得るために、そのウイルスを、BALB/cマウスにおいて致死性についてさらに滴定した。インフルエンザA/Vietnam/1203/2004(H5N1)ウイルスを、Centers for Disease Control(Atlanta,GA)のDr.Jackie Katzから入手した。マウスを致死量のそのウイルス(5MLD50,5PFU/マウス)に曝露した。この致死量は、以前に6〜13日目の間に死亡させたことがあり、この用量では10日目までに90〜100%の死亡率だった。
for Surveillance,Epidemiology and Control of Influenza,CDCから入手した。ウイルスストックを作製するために、2mM L−グルタミン、10mM HEPES、100U/mLペニシリン、100μg/mLストレプトマイシンおよび1μg/mLトリルスルホニルフェニルアラニルクロロメチルケトン(TPCK)処理トリプシン(USB Corp.;Santa Clara,CA)が補充されたDMEM中でMDCK細胞を低感染効率(MOI)で感染させた。細胞を37℃、5%CO2で48時間インキュベートし、その後、Beckman GS−6R遠心分離機を用いて900×gで10分間遠心分離することによって上清を回収した。ウイルスストックを等分し、−80℃で凍結した。
Ther.4,143−149(1999);Hayden,F.G.ら、Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza.JAMA 282,1240−1246(1999)。生のインフルエンザA/Wisconsin/67/2005(H3N2)チャレンジ株ウイルスを接種された健常志願者におけるA形の化合物(1)半水和物のHCl塩(本明細書中以後、この実施例において、簡潔に化合物(1))のランダム化二重盲検プラセボ対照単施設研究を行った。被験体に、1日量のプラセボ(N=33)または化合物(1)のいずれかを1日1回(QD)で、5回投与した(未希釈の化合物(1)からなるカプセルの形態で):1日目に100mg(N=16)、400mg(N=19)もしくは900mg、続いて、2〜5日目に600mg(N=20)、または1日目に1200mg、続いて、2〜5日目に600mg(N=18)。被験体は、1日3回鼻スワブを受け、1〜7日目に1日3回臨床症候についてのスコアカードをつけ、8日目に施設から解放され、およそ28日目に安全性の経過観察を受けた。鼻スワブを、細胞培養(主要解析)およびqRT−PCR(副次解析)によって、インフルエンザウイルスについてアッセイした。
注:統計学的に有意なP値(P<0.05)は太字である。
aヨンクヒール・タプストラ傾向検定からのAUCの用量反応傾向についてP=0.036。
bウィルコクソン順位和検定から算出されたP値。
cANOVAから算出されたP値。
dログランク検定から算出されたP値。
eヨンキー(Jonckherre)・テルプストラ傾向性検定からのAUCの用量反応傾向についてP=0.031。
fセロコンバージョンは、経過観察の来院時の抗インフルエンザ抗体価の、ベースラインと比較したときの≧4倍増加として定義される。フィッシャーの正確確率検定を用いて算出されたP値。
注:統計学的に有意なP値(P<0.05)は太字である。
bウィルコクソン順位和検定から算出されたP値。
cANOVAから算出されたP値。
dログランク検定から算出されたP値。
a1日目における900mgの単回の負荷量および2〜5日目におけるqdの600mg。
b1日目における1200mgの単回の負荷量および2〜5日目におけるqdの600mg。
c有効性の解析において定義されたようなインフルエンザ様疾病を本文に列挙されたパラメータに基づいて評価した。インフルエンザ様疾病のAEは、医師によって判定された。
and Editors,2nd Ed.,Washington,D.C.:American Chemical Society,1997を参照のこと。
1H), 4.30 - 3.85 (m, 2H), 2.89 (d, J =
6.8 Hz, 1H), 1.59 - 0.96 (m, 4H).
HClを加えることにより、pHをおよそ6.5に調整した。生成物をEtOAcで抽出した。有機相をMgSO4で乾燥し、濾過し、真空中で濃縮することにより、所望の生成物(1)を得た(NMR、LC/MSおよびHPLCによって97.5%の純度):1H NMR (300 MHz, d6−DMSO) δ 12.30 (d, J =
14.2 Hz, 2H), 8.79 − 7.94 (m, 4H), 7.58
(s, 1H), 4.68 (s, 1H), 2.84 (s, 1H), 1.85 (d, J = 85.0 Hz, 1H), 1.58 − 1.05 (m,
2H).
本発明は、その詳細な説明とともに記載されてきたが、前述の説明は、本発明を例証することを意図したものであって、本発明の範囲を限定することを意図しておらず、本発明の範囲は、添付の特許請求の範囲によって定義されることが理解されるべきである。他の態様、利点および改変は、添付の特許請求の範囲内である。
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