JP2019528276A - (s)−7−(1−アクリロイルピペリジン−4−イル)−2−(4−フェノキシフェニル)−4,5,6,7−テトラ−ヒドロピラゾロ[1,5−a]ピリミジン−3−カルボキサミドの結晶形、その調製、及びその使用 - Google Patents
(s)−7−(1−アクリロイルピペリジン−4−イル)−2−(4−フェノキシフェニル)−4,5,6,7−テトラ−ヒドロピラゾロ[1,5−a]ピリミジン−3−カルボキサミドの結晶形、その調製、及びその使用 Download PDFInfo
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- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
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- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
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- XMRIUEGHBZTNND-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1=CC=NC2=C(C(=O)N)C=NN21 XMRIUEGHBZTNND-UHFFFAOYSA-N 0.000 description 1
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- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
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Images
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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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Abstract
Description
酢酸エチル:ヘキサン=1:0.6-0.7(体積比);
酢酸エチル:ヘプタン=1:0.6-0.7(体積比);
酢酸エチル:シクロヘキサン=1:0.6-1.2(体積比);
酢酸メチル:ヘキサン=1:0.6-1.2(体積比);
トルエン:ヘキサン=1.0:0.2-0.4(体積比);
トルエン:シクロヘキサン=1.0:0.1-0.2(体積比);
酢酸メチル:シクロヘキサン=0.6-0.8:1.0(体積比);
IPAC:シクロヘキサン=1.0:0.2-1.0(体積比);又は
酢酸イソブチル:シクロヘキサン=1.0:0.2-1.0(体積比)。
式中、R1は水素又はアミノ保護基である。
ここでR1は水素、メチル、ベンジル、4−メトキシベンジル又は上述したような他の従来知られるアミノ保護基である。
ここでR1は水素、メチル、ベンジル、4−メトキシベンジル又は上述したような他の従来知られるアミノ保護基である。
定義
AcOH_酢酸
AEs_有害事象
BID_1日に2回
CLL_慢性リンパ性白血病
Con._濃縮(Concentrated)
D-DBTA_(2S,3S)-ジベンゾイル酒石酸
DDQ_2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン
DCM_ジクロロメタン
DIEA_N,N-ジイソプロピルエチルアミン
DLBCL_びまん性大細胞型B細胞リンパ腫
DMAc_N,N-ジメチルアセトアミド
DMF_N,N-ジメチルホルムアミド
DMF-DMA_N,N-ジメチルホルムアミドジメチルアセタール
DMSO_ジメチルスルホキシド
DSC_示差走査熱量測定
DVS_動的蒸気収着
EA_酢酸エチル,EtOAc
EDCI_1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド
EtOH_エタノール
FL_濾胞性リンパ腫
GC_ガスクロマトグラフ
GCMS_ガスクロマトグラフィー−質量分析
HOAc_酢酸
HOBt_ヒドロキシベンゾトリアゾール
HPLC_高速液体クロマトグラフィー
IPA_イソプロピルアルコール
IPAc_酢酸イソプロピル
IPC_インプロセス制御
KF_カールフィッシャー
L-DBTA_(2R,3R)-ジベンゾイル酒石酸
LOQ_数量化の限界
MCL_マントル細胞リンパ腫
MeCN又はACN_アセトニトリル
MeMgBr_臭化メチルマグネシウム
MeOH_メタノール
2-MeTHF_2-メチルテトラヒドロフラン
MIBE_4-メチル-2-ペンタノン
MsOH_メタンスルホン酸
MTBE_メチルターシャリーブチルエーテル
NHL_非ホジキンリンパ腫
NLT_以上(not less than)
NMP_1-メチル-2-ピロリドン
NMR_核磁気共鳴
NMT_以下(Not more than)
ORR_総合回答率
Pd_パラジウム
pH_水素イオン濃度
POA_フェノキシアセチル
QD_1日に1回
RH_相対湿度
SLL_小リンパ球性リンパ腫
RT_室温
TEA_トリエチルアミン
TGA_熱重量分析
THF_テトラヒドロフラン
TN_治療未経験
VGPR_非常に良好な部分奏効
XRPD_X線粉末回折
WM_ワルデンストロムマクログロブリン血症
実施例1(S)-7-(1-アクリロイルピペリジン-4-イル)-2-(4-フェノキシフェニル)-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド(化合物1)の調製及びその結晶形A
ステップ1:BG-2の合成
ステップ2:BG-3の合成
ステップ3:BG-4の合成
ステップ4から6:BG-8の合成
ステップ7:BG-9の合成
ステップ8:BG-10の合成
ステップ9:BG-11の合成
ステップ10:BG-11Aの合成
ステップ11:BG-11Bの合成
ステップ12:BG-11Cの合成
ステップ12:BG-11D(代替中間体)の合成
ステップ13:BG-12の合成
ステップ14:BG-13の合成
工程15:(S)-7-(1-アクリロイルピペリジン-4-イル)-2-(4-フェノキシフェニル)-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミドの合成(化合物1)
ステップ15:(S)-7-(1-アクリロイルピペリジン-4-イル)-2-(4-フェノキシフェニル)-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミドの合成(化合物1、代替法)
ステップ16:化合物1の結晶形Aの調製
実施例2 化合物1の結晶形Aの製造
実施例3 化合物1の結晶形Aの調製(貧溶媒添加)
実施例5 化合物1の結晶形Aの安定性試験及び化合物1の純度
(1)物理的安定性試験
(2)吸湿試験
(3)化合物1の純度を向上させるための形態Aによる結晶化/再結晶化。
実施例6 重水素標識した(S)-7-(1-アクリロイルピペリジン-4-イル)-2-(4-フェノキシフェニル)-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミドの調製(重水素標識化合物1)
実施例7 化合物1の多形の研究
(1)非晶形からの多形の研究−非晶形の化合物1からの形態Aの調製
ポリマー混合物B:ポリカプロラクトン(PCL)、ポリエチレングリコール(PEG)、ポリ(メチルメタクリレート)(PMMA)、アルギン酸ナトリウム(SA)、及びヒドロキシエチルセルロース(HEC)(質量比1:1:1:1:1)。
実施例8 化合物1の絶対配置の決定
BG-13の単結晶の作製
化合物1の絶対配置
実施例11 効力試験
テスト1:キナーゼの阻害と選択性
方法:
(1)BTKキナーゼ酵素試験
(2)生化学的キナーゼ選択性
結果:
試験2:結晶形AによるBTKpY223細胞試験
方法:
結果:
試験3:血液癌細胞系における腫瘍細胞増殖に対する結晶形Aの効果(Rec-1、Mino、JEKO-1及びTMD-8)
方法:
結果:
表17 血腫性腫瘍細胞増殖に対する結晶形Aによる阻害
試験4:マウスにおける結晶形Aの薬物動態学的研究
方法:
結果:
試験5:TMD-8異種移植モデルにおける結晶形Aの有効性試験
腫瘍移植方法:
結果:
試験6:全身REC-1異種移植モデルにおける結晶形Aの有効性試験
腫瘍移植方法:
%ILS=(MST−MST(ビヒクル))/MST(ビヒクル)×100
Gehan-Breslow-Wilcoxon検定を用いて各群間で統計分析を行った。P<0.05であれば統計的に有意であるものと考慮した。
結果:
テスト7:結晶形Aの毒性
試験8:結晶形Aの薬物動態
試験9:結晶形AのADME
実施例12:臨床試験研究
(1)進行中の臨床試験第I相進行性B細胞悪性腫瘍患者における化合物1の結果
1 最新の診断でリンパ球増加症と診断された5人の患者を含む;2 VGPRであった一人の患者を含む
注:CR =完全奏功;PR=部分奏功;SD=安定している疾患;PD=進行性疾患;ORR=奏効率
(2)ワルデンストロームマクログロブリン血症(WM)患者における化合物1の臨床試験第I相試験で継続中のものの結果
(3)慢性リンパ性白血病及び小リンパ球性リンパ腫(CLL/SLL)患者における化合物1の進行中の臨床試験第I相試験結果
Claims (42)
- 結晶形が無水物である、請求項1に記載の結晶形。
- X線粉末回折パターンが約14.8±0.2°、16.4±0.2°及び21.4±0.2°から独立して選択される2θ角度値を有する回折ピークを含むことを特徴とする、請求項1又は2に記載の結晶形。
- X線粉末回折パターンが約14.8±0.2°、15.6±0.2°、16.4±0.2°及び21.4±0.2°から独立して選択される2θ角度値を有する回折ピークを含むことを特徴とする、請求項1又は2に記載の結晶形。
- X線粉末回折パターンが約12.2±0.2°、12.9±0.2°、14.8±0.2°、15.6±0.2°、16.4±0.2°及び21.4±0.2°から独立して選択される2θ角度値を有する回折ピークを含むことを特徴とする、請求項1又は2に記載の結晶形。
- X線粉末回折パターンが約12.2±0.2°、12.9±0.2°、14.8±0.2°、15.6±0.2°、16.4±0.2°、17.7±0.2°、18.5±0.2°、20.7±0.2°及び21.4±0.2°から独立して選択される2θ角度値を有する回折ピークを含むことを特徴とする、請求項1又は2に記載の結晶形。
- 結晶形が、実質的に図1に記載のX線粉末回折パターンを有する、請求項1又は2に記載の結晶形。
- 結晶形の融点が139±2℃(開始温度)であることを特徴とする、請求項2〜7のいずれかに記載の結晶形。
- 結晶形が、実質的に図2に記載のDSCを示すことを特徴とする、請求項2〜7のいずれかに記載の結晶形。
- 結晶形が、実質的に図3に記載のTGAを示すことを特徴とする、請求項2〜7のいずれかに記載の結晶形。
- 結晶形が、純度>85%、又は純度>95%、又は純度>99%により特徴付けられる、請求項1〜7のいずれかに記載の結晶形。
- 前記結晶形がa=16.7939(4)Å、b=7.9871(2)Å、c=23.5438(5)Å、アルファ=90.00°、ベータ=108.0460(10)°、ガンマ=90.00°からなる単位格子寸法を有することを特徴とする、請求項12に記載の結晶形。
- アミノ保護基が、アセチル、プロピオニル、ブチリル、フェニルアセチル、ベンゾイル、トルイル、フェノキシアセチル、メトキシカルボニル、エトキシカルボニル、2,2,2-トリクロロエトキシカルボニル、tert-ブチルオキシカルボニル、2-ヨードエトキシカルボニル、カルボベンゾキシ、4-メトキシベンジルオキシカルボニル、(フルオレン-9-イルメトキシ)カルボニル、4-メトキシ-2,3,6-トリメチルベンゼンスルホニル、ベンジル、メチル及び4-メトキシベンジルから選択される、請求項14に記載の方法。
- 前記触媒が中性触媒系又はカチオン触媒系である、請求項14に記載の方法。
- 前記キラル酸が、L-リンゴ酸、D-リンゴ酸、L-マンデル酸、D-マンデル酸、L-カンファースルホン酸、D-カンファースルホン酸、L-酒石酸、D-酒石酸、L-DBTA、、D-DBTA、、L-DTTA及びD-DTTAから選択される、請求項17又は18に記載の方法。
- 請求項2〜7のいずれかに記載の結晶形を調製する方法であって、化合物1をDCMに溶解し、溶媒EAに交換し、EA/MTBEにてステップを経て目的の結晶形を得る方法。
- 請求項2〜7のいずれかに記載の結晶形を調製する方法であって、化合物1をEAに溶解し、ヘキサンを添加するステップを経て目的の結晶形を得る方法。
- 請求項2〜7のいずれかに記載の結晶形を調製する方法であって、化合物1を有機溶媒に溶解し、H2Oを添加するステップを経て目的の結晶形を得るところ、前記有機溶媒がアセトン又はDMAcである方法。
- 請求項2〜7のいずれかに記載の結晶形を調製する方法であって、請求項1〜7のいずれかに記載の結晶を有機溶媒に溶解し、H2Oを加えるステップを経て目的の結晶形を得るところ、前記有機溶媒がアセトン又はDMAcである方法。
- 請求項2〜7のいずれかに記載の結晶形を調製する方法であって、化合物1を有機溶媒に溶解し、n-ヘプタンを加えるステップを経て目的の結晶形を得るところ、前記有機溶媒がEtOAc、DCM、トルエン又は2-MeTHFである方法。
- 請求項2〜7のいずれかに記載の結晶形を調製する方法であって、請求項1〜7のいずれかに記載の結晶を有機溶媒に溶解し、n-ヘプタンを添加するステップを経て、目的の結晶形を得るところ、前記有機溶媒がEtOAc、DCM、トルエン又は2-MeTHFである方法。
- 請求項2〜7のいずれかに記載の結晶形を調製する方法であって、化合物1をアセトン又はEtOAcに溶解して溶液を得て、前記溶液をn-ヘプタンに入れ、室温で蒸発させるステップを経て、目的の結晶形を得る方法。
- 請求項2〜7のいずれかに記載の結晶形を調製する方法であって、請求項1〜7のいずれか1項に記載の結晶をアセトン又はEtOAcに溶解して溶液を得て、この溶液をn-ヘプタンに入れ、室温で蒸発させるステップを経て、目的の結晶形を得る方法。
- 化合物1又は請求項1〜7の結晶が、90%を超える、好ましくは97%を超えるee値を有する、請求項22〜29に記載の方法。
- 請求項1〜7のいずれかに記載の結晶形を治療有効量含み、さらに薬学的に許容される賦形剤を含む医薬組成物。
- 前記医薬組成物が経口投与で使用される、請求項31に記載の医薬組成物。
- 前記医薬組成物が請求項1〜7のいずれかに記載の結晶形を1重量%〜99重量%含有する、請求項31又は32のいずれかに記載の医薬組成物。
- 前記組成物が請求項1〜7のいずれかに記載の結晶形を1重量%〜70重量%含有する、請求項31に記載の医薬組成物。
- 前記組成物が請求項1〜7のいずれかに記載の結晶形を10重量%〜30重量%含有する、請求項31に記載の医薬組成物。
- 請求項1〜7のいずれかに記載の結晶形を対象に投与することにより、対象におけるBtk活性の異常に関連する疾患を治療する方法。
- 請求項1〜7のいずれかに記載の結晶形を対象に投与することにより、対象においてアレルギー性疾患、自己免疫疾患、炎症性疾患、癌、及びそれらの2つ以上の組み合わせから選択される疾患を治療する方法。
- 請求項1〜7のいずれかに記載の結晶形を対象に投与することにより、対象においてB細胞悪性腫瘍から選択されるB細胞増殖性疾患を治療する方法。
- 前記B細胞増殖性疾患が、リンパ腫、非ホジキンリンパ腫(NHL)、びまん性大細胞型B細胞リンパ腫(DLBCL)、マントル細胞リンパ腫(MCL)、濾胞性リンパ腫(FL)、慢性リンパ性白血病(CLL)、小リンパ性リンパ腫(SLL)、ワルデンストロームマクログロブリン血症(WM)、辺縁帯リンパ腫(MZL)、有毛細胞白血病(HCL)、バーキット様白血病(BL)、及びそれらの2つ以上の組み合わせから選択されるB細胞悪性腫瘍である請求項38に記載の方法。
- B細胞増殖性疾患が再発/難治性マントル細胞リンパ腫(R/R MCL)、再発/難治性慢性リンパ性白血病(R/R CLL)、再発/難治性の小リンパ球性リンパ腫(R/R SLL)、再発/難治性ワルデンストレームマクログロブリン血症(R/R WM)及びそれらの2つ以上の組み合わせから選択される再発/難治性B細胞悪性腫瘍である、請求項38に記載の方法。
- 請求項1〜7のいずれかに記載の結晶形を40mg〜320mg/日の用量で投与する、請求項38に記載の方法。
- 請求項1〜7のいずれかに記載の結晶形を1日2回(BID)160mg又は1日1回(QD)320mgの用量で投与する、請求項38に記載の方法。
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