JP2023011723A - 単回用量の調整済み注射用製剤 - Google Patents
単回用量の調整済み注射用製剤 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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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
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Abstract
Description
本出願は、参照により全体が本明細書に組み入れられる、2016年11月7日付で出願された米国特許仮出願第62/418,688号の恩典を主張する。
その薬学的に許容される塩、多形、および非晶質形態を含む式(I)の化合物を含有する、単回用量の調整済み製剤が、本明細書において提供される。それを調製するためのプロセスが本明細書においてさらに提供される。
式(I)
の化合物であるN-(5-(3-(7-(3-フルオロフェニル)-3H-イミダゾ[4,5-c]ピリジン-2-イル)-1H-インダゾール-5-イル)ピリジン-3-イル)-3-メチルブタンアミドは、Wnt阻害剤である。式(I)の化合物は、参照により全体が本明細書に組み入れられる米国特許第8,252,812号(特許文献1)に開示されているように調製することができる。その薬学的に許容される塩ならびに多形および非晶質形態を含む式(I)の化合物は、Wnt経路のおよび/またはWntシグナル伝達成分の1つもしくは複数の変異または調節異常による遺伝的疾患および神経学的状態/障害/疾患だけでなく、Wnt経路シグナル伝達の活性化によって特徴付けられる障害(例えば、がん、異常細胞増殖、血管新生、アルツハイマー病、肺疾患および変形性関節症)の処置、Wnt経路シグナル伝達によって媒介される細胞事象の調節においても用いることができる。その薬学的に許容される塩ならびに多形および非晶質形態を含む式(I)の化合物を含有する製剤、例えば単回用量の調整済み製剤が必要とされている。
式(I)
の化合物あるいはその薬学的に許容される塩または非晶質もしくは多形形態を含む単回用量の調整済み製剤を調製するためのプロセスが本明細書において提供され、該プロセスは、
(a) 水を含む水溶液を提供する段階;
(b) 式(I)の化合物あるいはその薬学的に許容される塩または非晶質もしくは多形形態を含むスラリーを提供する段階;
(c) 懸濁液を形成させるために水溶液とスラリーとを混合する段階; ならびに
(d) 単回用量の調整済み製剤を調製するために容器に懸濁液を充填する段階
を含む。
(b) 式(I)の化合物あるいはその薬学的に許容される塩または非晶質もしくは多形形態を含むスラリーを提供する段階;
(c) 懸濁液を形成させるために水溶液とスラリーとを混合する段階; ならびに
(d) 単回用量の調整済み製剤を調製するために容器に懸濁液を充填する段階
を含むプロセスによって調製された、式(I)
の化合物あるいはその薬学的に許容される塩または非晶質もしくは多形形態を含む単回用量の調整済み製剤も本明細書において提供される。
式(I)
の化合物あるいはその薬学的に許容される塩または非晶質もしくは多形形態を含む単回用量の調整済み製剤を調製するための方法であって、
(a) 水溶液を提供する段階;
(b) 式(I)の化合物あるいはその薬学的に許容される塩または非晶質もしくは多形形態を含むスラリーを提供する段階;
(c) 懸濁液を形成させるために該水溶液と該スラリーとを混合する段階; ならびに
(d) 単回用量の調整済み製剤を調製するために容器に該懸濁液を充填する段階
を含む、前記方法。
[本発明1002]
前記水溶液が濾過もしくは熱によって、または濾過および熱の組み合わせによって滅菌される、本発明1001の方法。
[本発明1003]
前記スラリーが熱によって滅菌される、本発明1001~1002のいずれかの方法。
[本発明1004]
懸濁液を形成させるための前記水溶液と前記スラリーとの混合が無菌的に行われ、続いて前記容器に無菌的に充填される、本発明1001~1003のいずれかの方法。
[本発明1005]
最終的な単回用量の調整済み製剤が、無菌である、本発明1001~1004のいずれかの方法。
[本発明1006]
前記水溶液が緩衝液を含む、本発明1001~1005のいずれかの方法。
[本発明1007]
前記水溶液が賦形剤を含む、本発明1001~1006のいずれかの方法。
[本発明1008]
緩衝液がリン酸緩衝液である、本発明1006~1007のいずれかの方法。
[本発明1009]
リン酸緩衝液が、二塩基性リン酸ナトリウム、一塩基性リン酸ナトリウム、一塩基性リン酸カリウム、二塩基性リン酸カリウム、およびそれらの混合物からなる群より選択される、本発明1008の方法。
[本発明1010]
リン酸緩衝液が、二塩基性リン酸ナトリウム七水和物と一塩基性リン酸ナトリウム一水和物との混合物である、本発明1008~1009のいずれかの方法。
[本発明1011]
賦形剤が界面活性剤、増粘剤、またはそれらの混合物を含む、本発明1007~1010のいずれかの方法。
[本発明1012]
増粘剤が水溶性セルロース誘導体である、本発明1011の方法。
[本発明1013]
界面活性剤がポリソルベートである、本発明1011~1012のいずれかの方法。
[本発明1014]
水溶性セルロース誘導体がカルボキシメチルセルロースナトリウムである、本発明1012~1013のいずれかの方法。
[本発明1015]
前記水溶液が、約0.01 g/kg~約50 g/kg、約0.1 g/kg~約50 g/kg、約1 g/kg~約25 g/kg、約1 g/kg~約10 g/kg、約1 g/kg~約7.5 g/kg、約1 g/kg~約5.5 g/kg、約1 g/kg~約2.5 g/kg、約2.5 g/kg~約50 g/kg、約5 g/kg~約50 g/kg、約10 g/kg~約50 g/kg、約25 g/kg~約50 g/kg、約2.5 g/kg~約7.5 g/kg、約5 g/kg~約10 g/kg、または約10 g/kg~約20 g/kgの増粘剤を含む、本発明1011~1014のいずれかの方法。
[本発明1016]
前記水溶液が約5.5 g/kgの増粘剤を含む、本発明1011~1015のいずれかの方法。
[本発明1017]
前記水溶液が、約0.01 g/kg~約5 g/kg、約0.01 g/kg~約2.5 g/kg、約0.01 g/kg~約1 g/kg、約0.01 g/kg~約0.75 g/kg、約0.01 g/kg~約0.5 g/kg、約0.01 g/kg~約0.25 g/kg、約0.025 g/kg~約5 g/kg、約0.05 g/kg~約5 g/kg、約1 g/kg~約5 g/kg、約0.1 g/kg~約5 g/kg、0.1 g/kg~約2.5 g/kg、約0.1 g/kg~約1 g/kg、約0.1 g/kg~約0.75 g/kg、約0.1 g/kg~約0.5 g/kg、約0.1 g/kg~約0.25 g/kg、約0.25 g/kg~約5 g/kg、約0.5 g/kg~約5 g/kg、約1 g/kg~約5 g/kg、約2.5 g/kg~約5 g/kg、約0.25 g/kg~約0.75 g/kg、約0.5 g/kg~約1 g/kg、または約1 g/kg~約2 g/kgの界面活性剤を含む、本発明1011~1016のいずれかの方法。
[本発明1018]
前記水溶液が約0.5 g/kgの界面活性剤を含む、本発明1011~1017のいずれかの方法。
[本発明1019]
前記水溶液が、約5.55 g/kgのカルボキシメチルセルロースナトリウムおよび約0.5 g/kgのポリソルベート80を含む、本発明1011~1018のいずれかの方法。
[本発明1020]
緩衝液がリン酸緩衝生理食塩水である、本発明1011~1019のいずれかの方法。
[本発明1021]
前記スラリーが、約0.001 g/kg~約5 g/kg、約0.001 g/kg~約2.5 g/kg、約0.001 g/kg~約1 g/kg、約0.001 g/kg~約0.75 g/kg、約0.001 g/kg~約0.5 g/kg、約0.001 g/kg~約0.25 g/kg、約0.001 g/kg~約0.01 g/kg、約0.01 g/kg~約5 g/kg、約0.01 g/kg~約2.5 g/kg、約0.01 g/kg~約1 g/kg、約0.01 g/kg~約0.75 g/kg、約0.01 g/kg~約0.5 g/kg、約0.01 g/kg~約0.25 g/kg、約0.1 g/kg~約2.5 g/kg、約0.1 g/kg~約1 g/kg、約0.1 g/kg~約0.75 g/kg、約0.1 g/kg~約0.5 g/kg、約0.1 g/kg~約0.25 g/kg、約0.25 g/kg~約5 g/kg、約0.5 g/kg~約5 g/kg、約1 g/kg~約5 g/kg、約2.5 g/kg~約5 g/kg、約0.25 g/kg~約0.75 g/kg、約0.5 g/kg~約1 g/kg、または約1 g/kg~約2 g/kgの式(I)の化合物あるいはその塩または非晶質もしくは多形形態を含む、本発明1001~1020のいずれかの方法。
[本発明1022]
前記スラリーが、約0.15 g/kg、約0.35 g/kg、約0.75 g/kgまたは約1.15 g/kgの式(I)の化合物あるいはその塩または非晶質もしくは多形形態を含む、本発明1001~1021のいずれかの方法。
[本発明1023]
式(I)の化合物が多形形態を含む、本発明1001~1022のいずれかの方法。
[本発明1024]
製造において用いられる多形が、形態1であり、かつ°2θ値6.8±0.2、12.4±0.2、および18.5±0.2にピークを含むX線粉末回折パターンを有する、本発明1001~1023のいずれかの方法。
[本発明1025]
式(I)の製造において用いられる化合物が、1重量%~約20重量%の水を有する形態1の非化学量論的または化学量論的水和物と形態1との混合物を含む、本発明1001~1024のいずれかの方法。
[本発明1026]
式(I)の製造において用いられる化合物が、式(I)の化合物の他の形態を約5重量%以下含む、本発明1001~1025のいずれかの方法。
[本発明1027]
式(I)の製造において用いられる化合物が、式(I)の化合物の他の形態を約1重量%以下含む、本発明1001~1026のいずれかの方法。
[本発明1028]
式(I)の製造において用いられる化合物が、式(I)の化合物の他の形態を約0.1重量%未満含む、本発明1001~1027のいずれかの方法。
[本発明1029]
前記スラリーが賦形剤を含む、本発明1001~1028のいずれかの方法。
[本発明1030]
賦形剤が界面活性剤を含む、本発明1029の方法。
[本発明1031]
界面活性剤がポリソルベートである、本発明1030の方法。
[本発明1032]
前記スラリーが、約0.01 g/kg~約5 g/kg、0.01 g/kg~約2.5 g/kg、約0.01 g/kg~約1 g/kg、約0.01 g/kg~約0.75 g/kg、約0.01 g/kg~約0.5 g/kg、約0.01 g/kg~約0.25 g/kg、約0.025 g/kg~約5 g/kg、約0.05 g/kg~約5 g/kg、約1 g/kg~約5 g/kg、約0.1 g/kg~約5 g/kg、0.1 g/kg~約2.5 g/kg、約0.1 g/kg~約1 g/kg、約0.1 g/kg~約0.75 g/kg、約0.1 g/kg~約0.5 g/kg、約0.1 g/kg~約0.25 g/kg、約0.25 g/kg~約5 g/kg、約0.25 g/kg~約2.5 g/kg、約0.25 g/kg~約0.75 g/kg、約0.5 g/kg~約5 g/kg、約0.5 g/kg~約2.5 g/kg、約0.5 g/kg~約1 g/kg、約1 g/kg~約5 g/kg、約2.5 g/kg~約5 g/kg、または約1 g/kg~約2 g/kgの界面活性剤を含む、本発明1030~1031のいずれかの方法。
[本発明1033]
前記スラリーが約0.5 g/kgの界面活性剤を含む、本発明1030~1032のいずれかの方法。
[本発明1034]
前記スラリーが、約0.15 g/kgの多形形態1または1重量%~約20重量%の水を有する形態1の非化学量論的もしくは化学量論的水和物と、約0.5 g/kgのポリソルベート80とを含む、本発明1030~1033のいずれかの方法。
[本発明1035]
前記スラリーが、約0.35 g/kgの多形形態1または1重量%~約20重量%の水を有する形態1の非化学量論的もしくは化学量論的水和物と、約0.5 g/kgのポリソルベート80とを含む、本発明1030~1034のいずれかの方法。
[本発明1036]
前記スラリーが、約0.75 g/kgの多形形態1または1重量%~約20重量%の水を有する形態1の非化学量論的もしくは化学量論的水和物と、約0.5 g/kgのポリソルベート80とを含む、本発明1030~1035のいずれかの方法。
[本発明1037]
前記スラリーが、約1.15 g/kgの多形形態1または1重量%~約20重量%の水を有する形態1の非化学量論的もしくは化学量論的水和物と、約0.5 g/kgのポリソルベート80とを含む、本発明1030~1036のいずれかの方法。
[本発明1038]
前記水溶液が濾過混合物である、本発明1001~1037のいずれかの方法。
[本発明1039]
前記水溶液が滅菌希釈剤を含む、本発明1001~1038のいずれかの方法。
[本発明1040]
前記水溶液が第1の滅菌混合物であり; 前記スラリーが第2の滅菌混合物であり; 該第1の滅菌混合物と該第2の滅菌混合物とを混合する段階を含む、本発明1001~1039のいずれかの方法。
[本発明1041]
約0.005 mg/mL~約2.5 mg/mL、約0.01 mg/mL~約2.0 mg/mL、約0.01 mg/mL~約1 mg/mL、約0.01 mg/mL~約0.5 mg/mL、約0.01 mg/mL~約0.2 mg/mL、または約0.015 mg/mL~約0.115 mg/mLの式(I)の化合物あるいはその塩または非晶質もしくは多形形態を含む懸濁液を形成させるために前記水溶液と前記スラリーとが混合される、本発明1001~1040のいずれかの方法。
[本発明1042]
前記容器が、約0.005 mg/mL~約2.5 mg/mL、約0.005 mg/mL~約2 mg/mL、約0.001 mg/mL~約2 mg/mL、約0.01 mg/mL~約1.8 mg/mL、約0.015 mg/mL~約0.115、約0.025 mg/mL~約1.6 mg/mL、約0.05 mg/mL~約1.5 mg/mL、約0.075 mg/mL~約1.25 mg/mL、約0.1 mg/mL~約1 mg/mL、または約0.25 mg/mL~約0.75 mg/mLの式(I)の化合物あるいはその塩または非晶質もしくは多形形態を含む懸濁液を含む、本発明1001~1041のいずれかの方法。
[本発明1043]
前記容器が、バイアル、瓶、アンプル、およびシリンジからなる群より選択される、本発明1001~1042のいずれかの方法。
[本発明1044]
バイアルが、ガラスバイアル、またはポリエチレン、ポリプロピレン、ポリオレフィン、ポリエチレンテレフタレート、ポリエチレンテレフタレートG、ポリ(塩化ビニル)、およびそれらの混合物で作られたプラスチックバイアルである、本発明1043の方法。
[本発明1045]
前記容器が、1 mL、2 mL、3 mL、4 mL、5 mL、6 mL、7 mL、8 mL、9 mL、または10 mLの容量を有する、本発明1001~1044のいずれかの方法。
[本発明1046]
前記容器が3 mLのポリプロピレンバイアルである、本発明1001~1045のいずれかの方法。
[本発明1047]
混合する段階が無菌的に行われる、本発明1001~1046のいずれかの方法。
[本発明1048]
充填する段階が無菌的に行われる、本発明1001~1047のいずれかの方法。
[本発明1049]
充填された前記容器を最終的に滅菌する段階をさらに含む、本発明1001~1048のいずれかの方法。
[本発明1050]
(a) 水を含む水溶液を提供する段階;
(b) 式(I)の化合物あるいはその薬学的に許容される塩または非晶質もしくは多形形態を含むスラリーを提供する段階;
(c) 懸濁液を形成させるために該水溶液と該スラリーとを混合する段階; ならびに
(d) 単回用量の調整済み製剤を調製するために容器に該懸濁液を充填する段階
を含む方法によって調製された、式(I)
の化合物あるいはその薬学的に許容される塩または非晶質もしくは多形形態を含む単回用量の調整済み製剤。
[本発明1051]
前記水溶液が緩衝液を含む、本発明1050の製剤。
[本発明1052]
前記水溶液が賦形剤を含む、本発明1050~1051のいずれかの製剤。
[本発明1053]
緩衝液がリン酸緩衝液である、本発明1051~1052のいずれかの製剤。
[本発明1054]
リン酸緩衝液が、二塩基性リン酸ナトリウム、一塩基性リン酸ナトリウム、一塩基性リン酸カリウム、二塩基性リン酸カリウム、およびそれらの混合物からなる群より選択される、本発明1051~1053のいずれかの製剤。
[本発明1055]
リン酸緩衝液が、二塩基性リン酸ナトリウム七水和物と一塩基性リン酸ナトリウム一水和物との混合物である、本発明1051~1054のいずれかの製剤。
[本発明1056]
賦形剤が界面活性剤、増粘剤、またはそれらの混合物を含む、本発明1052~1055のいずれかの製剤。
[本発明1057]
増粘剤が水溶性セルロース誘導体である、本発明1056の製剤。
[本発明1058]
界面活性剤がポリソルベートである、本発明1056~1057のいずれかの製剤。
[本発明1059]
セルロース誘導体がカルボキシメチルセルロースナトリウムである、本発明1057~1058のいずれかの製剤。
[本発明1060]
前記水溶液が、約0.0.01 g/kg~約50 g/kg、約1.0 g/kg~約50 g/kg、約1 g/kg~約25 g/kg、約1 g/kg~約10 g/kg、約1 g/kg~約7.5 g/kg、約1 g/kg~約5.5 g/kg、約1 g/kg~約2.5 g/kg、約2.5 g/kg~約50 g/kg、約5 g/kg~約50 g/kg、約10 g/kg~約50 g/kg、約25 g/kg~約50 g/kg、約2.5 g/kg~約7.5 g/kg、約5 g/kg~約10 g/kg、または約10 g/kg~約20 g/kgの増粘剤を含む、本発明1057~1059のいずれかの製剤。
[本発明1061]
前記水溶液が約5.5 g/kgの増粘剤を含む、本発明1057~1060のいずれかの製剤。
[本発明1062]
前記水溶液が、約0.01 g/kg~約5 g/kg、約0.01 g/kg~約2.5 g/kg、約0.01 g/kg~約1 g/kg、約0.01 g/kg~約0.75 g/kg、約0.01 g/kg~約0.5 g/kg、約0.01 g/kg~約0.25 g/kg、約0.025 g/kg~約5 g/kg、約0.05 g/kg~約5 g/kg、約1 g/kg~約5 g/kg、約0.1 g/kg~約5 g/kg、0.1 g/kg~約2.5 g/kg、約0.1 g/kg~約1 g/kg、約0.1 g/kg~約0.75 g/kg、約0.1 g/kg~約0.5 g/kg、約0.1 g/kg~約0.25 g/kg、約0.25 g/kg~約5 g/kg、約0.5 g/kg~約5 g/kg、約1 g/kg~約5 g/kg、約2.5 g/kg~約5 g/kg、約0.25 g/kg~約0.75 g/kg、約0.5 g/kg~約1 g/kg、または約1 g/kg~約2 g/kgの界面活性剤を含む、本発明1057~1061のいずれかの製剤。
[本発明1063]
前記水溶液が約0.5 g/kgの界面活性剤を含む、本発明1057~1062のいずれかの製剤。
[本発明1064]
前記水溶液が、約5.55 g/kgのカルボキシメチルセルロースナトリウムおよび約0.5 g/kgのポリソルベート80を含む、本発明1057~1063のいずれかの製剤。
[本発明1065]
緩衝液がリン酸緩衝生理食塩水である、本発明1053~1064のいずれかの製剤。
[本発明1066]
前記スラリーが、約0.001 g/kg~約5 g/kg、約0.001 g/kg~約2.5 g/kg、約0.001 g/kg~約1 g/kg、約0.001 g/kg~約0.75 g/kg、約0.001 g/kg~約0.5 g/kg、約0.001 g/kg~約0.25 g/kg、約0.001 g/kg~約0.01 g/kg、約0.01 g/kg~約5 g/kg、約0.01 g/kg~約2.5 g/kg、約0.01 g/kg~約1 g/kg、約0.01 g/kg~約0.75 g/kg、約0.01 g/kg~約0.5 g/kg、約0.01 g/kg~約0.25 g/kg、約0.1 g/kg~約2.5 g/kg、約0.1 g/kg~約1 g/kg、約0.1 g/kg~約0.75 g/kg、約0.1 g/kg~約0.5 g/kg、約0.1 g/kg~約0.25 g/kg、約0.25 g/kg~約5 g/kg、約0.5 g/kg~約5 g/kg、約1 g/kg~約5 g/kg、約2.5 g/kg~約5 g/kg、約0.25 g/kg~約0.75 g/kg、約0.5 g/kg~約1 g/kg、または約1 g/kg~約2 g/kgの式(I)の化合物あるいはその塩または非晶質もしくは多形形態を含む、本発明1050~1065のいずれかの製剤。
[本発明1067]
前記スラリーが、約0.15 g/kg、約0.35 g/kg、または約1.15 g/kgの式(I)の化合物あるいはその塩または非晶質もしくは多形形態を含む、本発明1050~1066のいずれかの製剤。
[本発明1068]
式(I)の化合物が多形形態を含む、本発明1050~1067のいずれかの製剤。
[本発明1069]
製造において用いられる多形が、形態1であり、かつ°2θ値6.8±0.2、12.4±0.2、および18.5±0.2にピークを含むX線粉末回折パターンを有する、本発明1050~1068のいずれかの製剤。
[本発明1070]
式(I)の化合物が、1重量%~約20重量%の水を有する形態1の非化学量論的または化学量論的水和物と形態1との混合物を含む、本発明1050~1069のいずれかの製剤。
[本発明1071]
式(I)の化合物が、式(I)の化合物の他の形態を約5重量%以下含む、本発明1050~1070のいずれかの製剤。
[本発明1072]
式(I)の化合物が、式(I)の化合物の他の形態を約1重量%以下含む、本発明1050~1071のいずれかの製剤。
[本発明1073]
式(I)の化合物が、式(I)の化合物の他の形態を約0.1重量%未満含む、本発明1050~1072のいずれかの製剤。
[本発明1074]
前記スラリーが賦形剤を含む、本発明1050~1073のいずれかの製剤。
[本発明1075]
賦形剤が界面活性剤を含む、本発明1074の製剤。
[本発明1076]
界面活性剤がポリソルベートである、本発明1075の製剤。
[本発明1077]
前記スラリーが、約0.01 g/kg~約5 g/kg、0.01 g/kg~約2.5 g/kg、約0.01 g/kg~約1 g/kg、約0.01 g/kg~約0.75 g/kg、約0.01 g/kg~約0.5 g/kg、約0.01 g/kg~約0.25 g/kg、約0.025 g/kg~約5 g/kg、約0.05 g/kg~約5 g/kg、約1 g/kg~約5 g/kg、約0.1 g/kg~約5 g/kg、0.1 g/kg~約2.5 g/kg、約0.1 g/kg~約1 g/kg、約0.1 g/kg~約0.75 g/kg、約0.1 g/kg~約0.5 g/kg、約0.1 g/kg~約0.25 g/kg、約0.25 g/kg~約5 g/kg、約0.25 g/kg~約2.5 g/kg、約0.25 g/kg~約0.75 g/kg、約0.5 g/kg~約5 g/kg、約0.5 g/kg~約2.5 g/kg、約0.5 g/kg~約1 g/kg、約1 g/kg~約5 g/kg、約2.5 g/kg~約5 g/kg、または約1 g/kg~約2 g/kgの界面活性剤を含む、本発明1075~1076のいずれかの製剤。
[本発明1078]
前記スラリーが約0.5 g/kgの界面活性剤を含む、本発明1075~1077のいずれかの製剤。
[本発明1079]
前記スラリーが、約0.15 g/kgの多形形態1または1重量%~約20重量%の水を有する形態1の非化学量論的もしくは化学量論的水和物と、約0.5 g/kgのポリソルベート80とを含む、本発明1075~1078のいずれかの製剤。
[本発明1080]
前記スラリーが、約0.35 g/kgの主に多形形態1または1重量%~約20重量%の水を有する形態1の非化学量論的もしくは化学量論的水和物と、約0.5 g/kgのポリソルベート80とを含む、本発明1075~1079のいずれかの製剤。
[本発明1081]
前記スラリーが、約1.15 g/kgの主に多形形態1または1重量%~約20重量%の水を有する形態1の非化学量論的もしくは化学量論的水和物と、約0.5 g/kgのポリソルベート80とを含む、本発明1075~1080のいずれかの製剤。
[本発明1082]
前記水溶液が濾過混合物である、本発明1050~1081のいずれかの製剤。
[本発明1083]
前記水溶液が滅菌希釈剤を含む、本発明1050~1082のいずれかの製剤。
[本発明1084]
前記水溶液が第1の滅菌混合物であり; 前記スラリーが第2の滅菌混合物であり; 該第1の滅菌混合物と該第2の滅菌混合物とを混合する段階を含む、本発明1050~1083のいずれかの製剤。
[本発明1085]
約0.005 mg/mL~約2.5 mg/mL、約0.01 mg/mL~約2.0 mg/mL、約0.01 mg/mL~約1 mg/mL、約0.01 mg/mL~約0.5 mg/mL、約0.01 mg/mL~約0.2 mg/mL、または約0.015 mg/mL~約0.115 mg/mLの式(I)の化合物あるいはその塩または非晶質もしくは多形形態を含む懸濁液を形成させるために前記水溶液と前記スラリーとが混合される、本発明1050~1084のいずれかの製剤。
[本発明1086]
前記容器が、約0.005 mg/mL~約2.5 mg/mL、約0.005 mg/mL~約2 mg/mL、約0.001 mg/mL~約2 mg/mL、約0.01 mg/mL~約1.8 mg/mL、約0.015 mg/mL~約0.115、約0.025 mg/mL~約1.6 mg/mL、約0.05 mg/mL~約1.5 mg/mL、約0.075 mg/mL~約1.25 mg/mL、約0.1 mg/mL~約1 mg/mL、または約0.25 mg/mL~約0.75 mg/mLの式(I)の化合物あるいはその塩または非晶質もしくは多形形態を含む懸濁液を含む、本発明1050~1085のいずれかの製剤。
[本発明1087]
前記容器が、バイアル、瓶、アンプル、およびシリンジからなる群より選択される、本発明1050~1086のいずれかの製剤。
[本発明1088]
バイアルが、ガラスバイアル、またはポリエチレン、ポリプロピレン、ポリオレフィン、ポリエチレンテレフタレート、ポリエチレンテレフタレートG、ポリ(塩化ビニル)、およびそれらの混合物で作られたプラスチックバイアルである、本発明1087の製剤。
[本発明1089]
前記容器が、1 mL、2 mL、3 mL、4 mL、5 mL、6 mL、7 mL、8 mL、9 mL、または10 mLの容量を有する、本発明1050~1088のいずれかの製剤。
[本発明1090]
前記容器が3 mLのポリプロピレンバイアルである、本発明1050~1089のいずれかの製剤。
[本発明1091]
混合する段階が無菌的に行われる、本発明1050~1090のいずれかの製剤。
[本発明1092]
充填する段階が無菌的に行われる、本発明1050~1091のいずれかの製剤。
[本発明1093]
充填された前記容器が最終的に滅菌される、本発明1050~1092のいずれかの製剤。
[本発明1094]
その必要がある対象において変形性関節症を処置する方法であって、治療的有効量の本発明1050~1094のいずれかの単回用量の調整済み製剤を該対象に投与する段階を含む、前記方法。
[本発明1095]
投与が関節内投与である、本発明1094の方法。
[本発明1096]
前記製剤が1回投与される、本発明1094~1095のいずれかの方法。
[本発明1097]
前記製剤が2回以上投与され、各注射が約3ヶ月~約60ヶ月間隔てられる、本発明1094~1095のいずれかの方法。
[本発明1098]
前記製剤が月1回、3ヶ月に1回、6ヶ月に1回、または60ヶ月に1回投与される、本発明1094~1095および1097のいずれかの方法。
本明細書において提供されるプロセス、製剤、および使用の他の特徴および利点は、以下の詳細な説明および図面から、ならびに特許請求の範囲から明らかとなるであろう。
1. 定義
他に定義されない限り、本明細書において用いられる全ての技術的および科学的用語は、本開示が属する技術分野の当業者によって一般的に理解されるのと同じ意味を有する。方法および材料は、本開示で用いるために本明細書において記述される; 当技術分野において公知の他の適当な方法および材料を用いることもできる。材料、方法、および実施例は例示的なものにすぎず、限定的であることを意図しない。本明細書において言及された全ての刊行物、特許出願、特許、配列、データベースエントリ、および他の参考文献は、参照によりその全体が組み入れられる。矛盾がある場合、定義を含めて、本明細書が優先するものとする。
その塩ならびに非晶質および多形形態を含む式(I)
の化合物を含む単回用量の調整済み製剤を調製するためのプロセスが本明細書において提供される。このプロセスは、
(a) 水を含む水溶液を提供する段階;
(b) その塩ならびに非晶質および多形形態を含む式(I)の化合物を含むスラリーを提供する段階;
(c) 懸濁液を形成させるために水溶液とスラリーとを混合する段階; ならびに
(d) 単回用量の製剤を調製するために容器に懸濁液を無菌的に充填する段階
を含む。
本明細書において記述されるプロセスによって調製された、その薬学的に許容される塩ならびに非晶質および多形形態を含む式(I)の化合物を含む単回用量の調整済み薬学的製剤が本明細書において提供される。いくつかの態様では、製剤は単回用量の製剤として調製される。式(I)の化合物の多形形態から調製された薬学的製剤が本明細書において提供される。いくつかの態様では、多形形態は形態1である。いくつかの態様では、多形形態は形態1と形態9との混合物である。いくつかの態様では、多形は1重量%~約20重量%の水を有する形態1の非化学量論的または化学量論的水和物である。
0.01重量%~約0.5重量%の界面活性剤を含む。例えば、本明細書において提供される薬学的製剤は、リン酸緩衝生理食塩水中に式(I)の化合物、例えば形態1または1重量%~約20重量%の水を有する形態1の非化学量論的もしくは化学量論的水和物、約0.5重量%のカルボキシメチルセルロースナトリウムおよび約0.05重量%のポリソルベート80を含むことができる。
本明細書ではキットも提供される。典型的には、キットは、本明細書において記述される1つまたは複数の製剤、例えば、その非晶質および多形形態を含む式(I)の化合物を含む、本明細書において提供されるプロセスによって調製された単回用量の調整済み製剤を含む。ある種の態様では、キットは、例えば本明細書において提供される製剤を送達または投与するための、1つまたは複数の送達システム、およびキットの使用説明書(例えば、患者を処置するための取扱説明書)を含むことができる。いくつかの態様では、キットは、本明細書において記述される製剤、および骨もしくは軟骨疾患または変形性関節症を有する患者に内容物が投与されるべきであることを示すラベルを含むことができる。本明細書において提供される式(I)の化合物の実際の用量は、特定の化合物、および処置されるべき状態に依存する; 適切な用量の選択は、十分に当業者の知識の範囲内である。
対象における変形性関節症の処置のための方法が提供される。本方法は、その塩および非晶質または多形形態を含む式(I)の化合物を含む本明細書において提供される単回用量の調整済み製剤の治療的有効量を対象に投与する段階を含む。いくつかの態様では、製剤は、本明細書において提供されるプロセスによって調製される。いくつかの態様では、本明細書において提供される方法は、その塩ならびに非晶質および多形形態を含む式(I)の化合物の治療的有効量を含む単回用量の調整済み薬学的製剤の関節内投与を含む。いくつかの態様では、本明細書において提供される方法は、本明細書において提供されるプロセスによって調製された単回用量の調整済み薬学的製剤の関節内投与を含む。いくつかの態様では、多形形態は形態1である。いくつかの態様では、多形形態は1重量%~約20重量%の水を有する形態1の非化学量論的または化学量論的水和物である。
0.015 mg/mL、0.025 mg/mLまたは0.115 mg/mLのいずれかの式(I)の化合物の多形形態1を含有する単回用量の調整済み製剤を調製した。式(I)の化合物は、参照により全体が本明細書に組み入れられるUS 2013/0267495に提供されているプロセスにしたがって調製された。形態1の多形は、本明細書において記述されているように調製された。
水、カルボキシメチルセルロースナトリウム(CMC) (5.55 g/kg)、ポリソルベート80 (0.50 g/kg)、一塩基性リン酸ナトリウム一水和物(0.268 g/kg)、二塩基性リン酸ナトリウム七水和物(2.44 g/kg)、および塩化ナトリウム(9.11 g/kg)を300 Lの第1のタンクに加えた。次に、第1のタンク中の水溶液を、0.2 μmのポリエーテルスルホン(PES)フィルタを通して第2のタンク中に濾過し、そこでそれをバルク滅菌した。0.15 g/kgの式(I)の化合物の多形形態1、注射用水、および0.5 g/kgのポリソルベート80を30 Lの第3のタンクに加えて、15 μg/mLの式(I)の化合物を含有するスラリーを形成させた。スラリーを塔頂(overhead)蒸気圧によって滅菌し、次いで水溶液を含有する第2のタンクに加えた。スラリーを30 Hzで均質化し、オーバーキルサイクル(F0≧30)の原理を用いて製造した。混合物を滅菌希釈剤と無菌的に混合して、0.015 mg/mLの式(I)の化合物の濃度で懸濁液を形成させた。底部TCによりモニターされるバルク溶液温度を250°Fに維持し、塔頂圧力をタンクジャケットに導入された蒸気圧より高く維持した(およそ5 psi超)。タンク上方のTCをモニターするミキサー隣のトップバルブのガス抜き中の塔頂圧力を維持するために、蒸気をエアフィルタによりタンク中に導入して圧力および高温を維持した。蒸気圧をモニターし、バルク滅菌を実施した。次いでWeiler 624 BFS機を用い、懸濁液を、目標容量2.5 mLおよび終濃度0.015 mg/mLの式(I)の化合物で、3 mLのポリプロピレンバイアル中に無菌的に充填した。各バイアルは、リン酸緩衝生理食塩水2 mL中に式(I)の化合物の形態1を0.03 mg含有していた。バイアルにラベルを付けて包装した。
水、カルボキシメチルセルロースナトリウム(CMC) (5.55 g/kg)、ポリソルベート80 (0.50 g/kg)、一塩基性リン酸ナトリウム一水和物(0.268 g/kg)、二塩基性リン酸ナトリウム七水和物(2.44 g/kg)、および塩化ナトリウム(9.11 g/kg)を300 Lの第1のタンクに加えた。次に、第1のタンク中の水溶液を、0.2 μmのポリエーテルスルホン(PES)フィルタを通して第2のタンク中に濾過し、そこでそれをバルク滅菌した。0.35 g/kgの式(I)の化合物の多形形態1、注射用水、および0.5 g/kgのポリソルベート80を30 Lの第3のタンクに加えて、35 μg/mLの式(I)の化合物を含有するスラリーを形成させた。スラリーを塔頂蒸気圧によって滅菌し、次いで水溶液を含有する第2のタンクに加えた。スラリーを30 Hzで均質化し、オーバーキルサイクル(F0≧30)の原理を用いて製造した。混合物を滅菌希釈剤と無菌的に混合して、0.035 mg/mLの式(I)の化合物の濃度で懸濁液を形成させた。底部TCによりモニターされるバルク溶液温度を250°Fに維持し、塔頂圧力をタンクジャケットに導入された蒸気圧より高く維持した(およそ5 psi超)。タンク上方のTCをモニターするミキサー隣のトップバルブのガス抜き中の塔頂圧力を維持するために、蒸気をエアフィルタによりタンク中に導入して圧力および高温を維持した。蒸気圧をモニターし、バルク滅菌を実施した。次いでWeiler 624 BFS機を用い、懸濁液を、目標容量2.5 mLおよび終濃度0.035 mg/mLの式(I)の化合物で、3 mLのポリプロピレンバイアル中に無菌的に充填した。各バイアルは、リン酸緩衝生理食塩水2 mL中に式(I)の化合物の形態1を0.07 mg含有していた。バイアルにラベルを付けて包装した。
水、カルボキシメチルセルロースナトリウム(CMC) (5.55 g/kg)、ポリソルベート80 (0.50 g/kg)、一塩基性リン酸ナトリウム一水和物(0.268 g/kg)、二塩基性リン酸ナトリウム七水和物(2.44 g/kg)、および塩化ナトリウム(9.11 g/kg)を300 Lの第1のタンクに加えた。次に、第1のタンク中の水溶液を、0.2 μmのポリエーテルスルホン(PES)フィルタを通して第2のタンク中に濾過し、そこでそれをバルク滅菌した。0.75 g/kgの式(I)の化合物の多形形態1、注射用水、および0.5 g/kgのポリソルベート80を30 Lの第3のタンクに加えて、75 μg/mLの式(I)の化合物を含有するスラリーを形成させた。スラリーを塔頂蒸気圧によって滅菌し、次いで水溶液を含有する第2のタンクに加えた。スラリーを30 Hzで均質化し、オーバーキルサイクル(F0≧30)の原理を用いて製造した。混合物を滅菌希釈剤と無菌的に混合して、0.075 mg/mLの式(I)の化合物の濃度で懸濁液を形成させた。底部TCによりモニターされるバルク溶液温度を250°Fに維持し、塔頂圧力をタンクジャケットに導入された蒸気圧より高く維持した(およそ5 psi超)。タンク上方のTCをモニターするミキサー隣のトップバルブのガス抜き中の塔頂圧力を維持するために、蒸気をエアフィルタによりタンク中に導入して圧力および高温を維持した。蒸気圧をモニターし、バルク滅菌を実施した。次いでWeiler 624 BFS機を用い、懸濁液を、目標容量2.5 mLおよび終濃度0.075 mg/mLの式(I)の化合物で、3 mLのポリプロピレンバイアル中に無菌的に充填した。各バイアルは、リン酸緩衝生理食塩水2 mL中に式(I)の化合物の形態1を0.15 mg含有していた。バイアルにラベルを付けて包装した。
水、カルボキシメチルセルロースナトリウム(CMC) (5.55 g/kg)、ポリソルベート80 (0.50 g/kg)、一塩基性リン酸ナトリウム一水和物(0.268 g/kg)、二塩基性リン酸ナトリウム七水和物(2.44 g/kg)、および塩化ナトリウム(9.11 g/kg)を300 Lの第1のタンクに加えた。次に、第1のタンク中の水溶液を、0.2 μmのポリエーテルスルホン(PES)フィルタを通して第2のタンク中に濾過し、そこでそれをバルク滅菌した。0.15 g/kgの式(I)の化合物の多形形態1、注射用水、および0.5 g/kgのポリソルベート80を30 Lの第3のタンクに加えて、115 μg/mLの式(I)の化合物を含有するスラリーを形成させた。スラリーを塔頂蒸気圧によって滅菌し、次いで水溶液を含有する第2のタンクに加えた。スラリーを30 Hzで均質化し、オーバーキルサイクル(F0≧30)の原理を用いて製造した。混合物を滅菌希釈剤と無菌的に混合して、0.115 mg/mLの式(I)の化合物の濃度で懸濁液を形成させた。底部TCによりモニターされるバルク溶液温度を250°Fに維持し、塔頂圧力をタンクジャケットに導入された蒸気圧より高く維持した(およそ5 psi超)。タンク上方のTCをモニターするミキサー隣のトップバルブのガス抜き中の塔頂圧力を維持するために、蒸気をエアフィルタによりタンク中に導入して圧力および高温を維持した。蒸気圧をモニターし、バルク滅菌を実施した。次いでWeiler 624 BFS機を用い、懸濁液を、目標容量2.5 mLおよび終濃度0.035 mg/mLの式(I)の化合物で、3 mLのポリプロピレンバイアル中に無菌的に充填した。各バイアルは、リン酸緩衝生理食塩水2 mL中に式(I)の化合物の形態1を0.23 mg含有していた。バイアルにラベルを付けて包装した。
式(I)の化合物の多形形態は、上記の実施例1において記述されている調整済み製剤において用いられた。多形スクリーニングを式(I)の化合物について行って、溶解性、多形性、および熱力学的安定性を判定した。
式(I)の出発固体化合物のX線粉末回折(XRD)、示差走査熱量測定(DSC)、および熱重量分析(TGA)走査図は、出発固体が結晶性材料であり、形態1と1重量%~約20重量%の水を有する形態1の非化学量論的または化学量論的水和物との混合物であることを示した。DSC走査図(図12B)によれば、固体は50℃~100℃での広い吸熱を示し、284℃での鋭い発熱も示し、固体は最終的に364℃で融解した。TGA走査図(図12C)によれば、100℃の前に1.4%の重量減少が観察された。
形態1を生成した実験を以下の表6に示す。一般に、形態1は形態13または形態12の乾燥により得られた。形態1は脱水水和物と見なされうる。多くの二元溶媒(5%の水を有する)中での再スラリー化により形態1が生成された。残留固体の純度は98.9%であった。形態1(1つの試料)固体のKFは5.8%、形態1固体の残留MeOHは0.01%であった。完全乾燥形態1固体のTGA走査を行った(図1C)。100℃の前に0.33%の重量減少が観察された。
形態2、2*、および2**を生成した実験を以下の表8に示す。形態2、2*、および2**のXRD走査を行った(図2A、図2D、および図2Gはそれぞれ形態2、2*、および2**のXRD走査図を示す)。形態2および2*のXRDピークをそれぞれ以下の表9および表10に示す。DSC走査も行った(図2B、図2E、および図2Hはそれぞれ形態2、2*、および2**のDSC走査図を示す)。DSC走査図によれば、形態2、2*、および2**はそれぞれ、50℃~100℃での広い吸熱、ならびに363℃で融解する前の複数の吸熱および発熱を示した。100℃の前での広い吸熱は、固体に水/溶媒が含まれることが理由でありうる。形態2はアセトニトリルから得られ、形態2*はエタノールから得られ、形態2**はn-プロパノール/5%水から得られた。
形態3を生成した実験を以下の表11に示す。形態3のXRDおよびDSC走査図を取得した(それぞれ図3Aおよび図3B)。以下の表12は形態3のXRDピークを示す。形態3のDSC走査図から複数の発熱および吸熱が観察された。
形態4、4*、および4**を生成した実験を以下の表13に示す。形態4、4*、および4**のXRDを取得した(それぞれ図4A、図4D、および図4G)。以下の表14および表15はそれぞれ形態4および形態4*のXRDピークを示す。形態4、4*、および4**のDSC走査も行った(それぞれ図4B、図4E、および図4H)。DSC走査図によれば、形態4は50℃~100℃で広い吸熱を、続いて複数の吸熱/発熱を示し、次に約367℃で融解した。形態4*および4**は形態4と同様のDSCパターンを示した。
形態5および5*を生成した実験を以下の表16に示す。形態5および5*のXRD走査図を取得した(それぞれ図5Aおよび図5D)。形態5のXRDピークを以下の表17に示す。形態5のDSC走査も行い、走査図は50℃~100℃での広い吸熱、ならびに363℃で融解する前の複数の吸熱および発熱を示した(図5B)。
形態6を生成した実験を以下の表18に示す。形態6のXRDおよびDSC走査図を取得した(それぞれ図6Aおよび図6B)。DSC走査図によれば、固体は250℃で小さな発熱を、358℃で鋭い融解吸熱を示した。
形態7を生成した実験を以下の表19に示す。形態7のXRDおよびDSC走査図を取得した(それぞれ図7Aおよび図7B)。形態7のXRDピークを以下の表20に示す。DSC走査図によれば、固体は227℃および299℃で2つの発熱を、続いて365℃で融解吸熱を示した。形態7はXRD上で低い結晶化度を示した。DSC走査図上での二重発熱は、XRD走査図上で観察された低い結晶化度と関連している可能性がある。
形態8を生成した実験を以下の表21に示す。形態8のXRDおよびDSC走査図を取得した(それぞれ図8Aおよび図8B)。形態8のXRDピークを以下の表22に示す。DSC走査図によれば、固体は205℃および231℃で2つの吸熱を、続いて279℃で発熱を、続いて362℃で融解吸熱を示した。形態8はXRD走査図上で低い結晶化度を示した。DSC走査図上での二重発熱によって、XRD上で見られた低い結晶化度が確認される可能性がある(低結晶化度の材料はより高結晶化度の固体に変換される)。
形態9を生成した実験を以下の表23に示す。形態9のXRDおよびDSC走査図を取得した(それぞれ図9Aおよび図9B)。形態9のXRDピークを以下の表24に示す。DSC走査図によれば、固体は364℃で単一の融解吸熱を示した。形態9は、おおよその大きさ a [Å] = 17.135、b [Å] = 14.342、c [Å] = 10.186; α(deg)=90、β(deg)=95.99、γ(deg)=90、およびおおよその体積セル[Å3/セル] = 2,489.5、およびP21/c (14)と定義された空間群を有する、単純単斜晶系結晶構造を有する。
形態10および10*を生成した実験を以下の表25に示す。形態10および10*のXRD走査図を取得した(それぞれ図10Aおよび図10D)。形態10のXRDピークを以下の表26に示す。形態10および10*のDSC走査図も取得し、走査図は複数の吸熱/発熱を、続いて367℃での融解を示した(それぞれ図10Bおよび図10E)。
形態11および11*を生成した実験を以下の表27に示す。形態11および11*のXRD走査図を取得した(それぞれ図11Aおよび図11D)。形態11および形態11*のXRDピークをそれぞれ以下の表28および表29に示す。形態11および11*のDSC走査図も取得した(それぞれ図11Bおよび図11E)。DSC走査図によれば、固体は複数の吸熱/発熱を示し、最終的に368℃で融解した。両形態のXRDにおいて非晶質ハローが観察された。また、両形態のDSC上での二重発熱は、XRD走査図上で観察された非晶質ハローと関連している可能性がある。
形態13および形態12を生成した実験をそれぞれ以下の表30および表32に示す。形態12および13は、1重量%~約20重量%の水を有する形態1の非化学量論的水和物の例である。形態13および形態12のXRD走査図を取得した(それぞれ図13Aおよび図12A)。形態13のXRDピークを以下の表31に示す。形態13および形態12のDSC走査図も取得した(それぞれ図13Bおよび図12B)。DSC走査図によれば、形態13固体は50℃~100℃で広い吸熱を、続いて278℃で小さな発熱を、363℃で融解吸熱を示した。DSC走査図によれば、形態12固体は50℃~100℃で広い吸熱を、続いて283℃で鋭い発熱を、364℃で融解吸熱を示した。
溶媒和物1、2、および3を生成した実験を以下の表33に示す。溶媒和物1および2の固体を空気に終夜曝露した後、XRDで分析した。分析後、固体を50℃で減圧乾燥させ、次にXRDで再度分析した。
異なる形態の間での熱力学的安定性を解明するために、いくつかの競合的スラリー化実験を行った。形態1、形態2、形態2*、形態3、形態4、形態4*、形態4**、形態5、形態7、形態8、形態9、形態10、形態11、形態11*、および形態13(各10mg)を溶媒2mL中、室温および50℃の両方で混合およびスラリー化した。固体を3~5日間スラリー化した後、XRDで分析した。分析データによれば、形態2*が、MeOH系、EtOH系、およびアセトン系中、室温および50℃の両方で最も安定な形態であった。形態4または4*が、EA中、室温および50℃で最も安定であった。形態13が、水中、室温および50℃で最も安定であった。表34は、競合的スラリー化実験によるXRD走査結果を示す。
先の記述は、添付の特許請求の範囲によって定義される本開示の範囲を例示するものであって、限定するものではないよう意図されることが理解されるべきである。他の局面、利点、および改変は添付の特許請求の範囲内にある。
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Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102010611B1 (ko) | 2011-09-14 | 2019-08-13 | 사뮤메드, 엘엘씨 | 인다졸-3-카르복사미드 및 WNT/β-카테닌 신호생성 경로 저해제들로써의 이들 용도 |
PH12017500997A1 (en) | 2012-04-04 | 2018-02-19 | Samumed Llc | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
PT2770994T (pt) | 2012-05-04 | 2019-11-04 | Samumed Llc | 1h-pirazolo[3,4-b]piridinas e utilizações terapêuticas destas |
JP6355648B2 (ja) | 2013-01-08 | 2018-07-11 | サミュメッド リミテッド ライアビリティ カンパニー | Wntシグナル伝達経路の3−(ベンゾイミダゾール−2−イル)−インダゾール阻害剤およびそれらの治療的使用 |
WO2016040181A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
WO2016040190A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
WO2016040180A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
WO2016040185A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof |
WO2016040193A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
WO2016040184A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
US10329309B2 (en) | 2015-08-03 | 2019-06-25 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10463651B2 (en) | 2015-08-03 | 2019-11-05 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-indazoles and therapeutic uses thereof |
WO2017023972A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10519169B2 (en) | 2015-08-03 | 2019-12-31 | Samumed, Llc | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
WO2017024003A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
WO2017024021A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
US10206908B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
WO2017023987A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
WO2017023993A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-indol-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10383861B2 (en) | 2015-08-03 | 2019-08-20 | Sammumed, LLC | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10392383B2 (en) | 2015-08-03 | 2019-08-27 | Samumed, Llc | 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10206909B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10285983B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-B] pyridines and therapeutic uses thereof |
US10285982B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10604512B2 (en) | 2015-08-03 | 2020-03-31 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof |
WO2017079759A1 (en) | 2015-11-06 | 2017-05-11 | Samumed, Llc | 2-(1h-indazol-3-yl)-3h-imidazo[4,5-c]pyridines and their anti-inflammatory uses thereof |
SG10201912248RA (en) | 2016-06-01 | 2020-02-27 | Samumed Llc | Process for preparing n-(5-(3-(7-(3-fluorophenyl)-3h-imidazo[4,5-c]pyridin-2-yl)-1h-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide |
MX2019004616A (es) | 2016-10-21 | 2019-11-21 | Samumed Llc | Métodos de uso de indazol-3-carboxamidas y su uso como inhibidores de la ruta de señalización de wnt/b-catenina. |
MA46696A (fr) | 2016-11-07 | 2019-09-11 | Samumed Llc | Formulations injectables à dose unique prêtes à l'emploi |
US11040008B2 (en) * | 2018-04-04 | 2021-06-22 | Slayback Pharma Llc | Pharmaceutical compositions of meloxicam |
MX2024008076A (es) * | 2022-01-24 | 2024-07-12 | Lg Chem Ltd | Formulacion inyectable que contiene derivado de isoxazolina. |
Family Cites Families (164)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4164559A (en) | 1977-09-21 | 1979-08-14 | Cornell Research Foundation, Inc. | Collagen drug delivery device |
ES8401486A1 (es) | 1981-11-10 | 1983-12-01 | Wellcome Found | Un procedimiento para la preparacion de nuevos derivados de imidazo (4,5-c)piridina. |
US4474752A (en) | 1983-05-16 | 1984-10-02 | Merck & Co., Inc. | Drug delivery system utilizing thermosetting gels |
US4783443A (en) | 1986-03-03 | 1988-11-08 | The University Of Chicago | Amino acyl cephalosporin derivatives |
EP0410509A1 (en) | 1989-07-25 | 1991-01-30 | Duphar International Research B.V | New substituted 1H-indazole-3-carboxamides |
GB9414139D0 (en) | 1994-07-13 | 1994-08-31 | Smithkline Beecham Plc | Novel compounds |
US6440102B1 (en) | 1998-07-23 | 2002-08-27 | Durect Corporation | Fluid transfer and diagnostic system for treating the inner ear |
DE19853299C2 (de) | 1998-11-19 | 2003-04-03 | Thomas Lenarz | Katheter zur Applikation von Medikamenten in Flüssigkeitsräumen des menschlichen Innenohrs |
US6120484A (en) | 1999-02-17 | 2000-09-19 | Silverstein; Herbert | Otological implant for delivery of medicament and method of using same |
MXPA01011832A (es) | 1999-05-21 | 2002-06-21 | Squibb Bristol Myers Co | Inhibidores de cinasas, de pirrolotriazina. |
EP1194425B1 (de) | 1999-06-23 | 2005-08-10 | Aventis Pharma Deutschland GmbH | Substituierte benzimidazole |
TWI262914B (en) | 1999-07-02 | 2006-10-01 | Agouron Pharma | Compounds and pharmaceutical compositions for inhibiting protein kinases |
PE20010306A1 (es) | 1999-07-02 | 2001-03-29 | Agouron Pharma | Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa |
US6844367B1 (en) | 1999-09-17 | 2005-01-18 | Millennium Pharmaceuticals, Inc. | Benzamides and related inhibitors of factor Xa |
US6967023B1 (en) | 2000-01-10 | 2005-11-22 | Foamix, Ltd. | Pharmaceutical and cosmetic carrier or composition for topical application |
YU54202A (sh) | 2000-01-18 | 2006-01-16 | Agouron Pharmaceuticals Inc. | Jedinjenja indazola, farmaceutske smeše i postupci za stimulisanje i inhibiranje ćelijske proliferacije |
US6897231B2 (en) | 2000-07-31 | 2005-05-24 | Signal Pharmaceuticals, Inc. | Indazole derivatives as JNK inhibitors and compositions and methods related thereto |
US20050009876A1 (en) | 2000-07-31 | 2005-01-13 | Bhagwat Shripad S. | Indazole compounds, compositions thereof and methods of treatment therewith |
JP4105948B2 (ja) | 2000-09-15 | 2008-06-25 | バーテックス ファーマシューティカルズ インコーポレイテッド | プロテインキナーゼインヒビターとして有用なピラゾール化合物 |
US7105532B2 (en) | 2000-12-19 | 2006-09-12 | Smithkline Beecham Corporation | Pyrazolo[3,4-c]pyridines as gsk-3 inhibitors |
US20050192262A1 (en) | 2001-03-13 | 2005-09-01 | Tomas Hagstrom | Treatment of tumours |
AU2002259071A1 (en) | 2001-04-30 | 2002-11-11 | Vertex Pharmaceuticals Incorporated | Inhibitors of gsk-3 and crystal structures of gsk-3beta protein and protein complexes |
GB0115109D0 (en) | 2001-06-21 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
EP1401831A1 (en) | 2001-07-03 | 2004-03-31 | Chiron Corporation | Indazole benzimidazole compounds as tyrosine and serine/threonine kinase inhibitors |
US7642278B2 (en) | 2001-07-03 | 2010-01-05 | Novartis Vaccines And Diagnostics, Inc. | Indazole benzimidazole compounds |
WO2004043335A2 (en) | 2001-09-13 | 2004-05-27 | Genesoft, Inc. | Methods of treating infection by drug resistant bacteria |
US7101884B2 (en) | 2001-09-14 | 2006-09-05 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
US6648873B2 (en) | 2001-09-21 | 2003-11-18 | Durect Corp. | Aural catheter system including anchor balloon and balloon inflation device |
US6897208B2 (en) | 2001-10-26 | 2005-05-24 | Aventis Pharmaceuticals Inc. | Benzimidazoles |
WO2003035005A2 (en) | 2001-10-26 | 2003-05-01 | University Of Connecticut | Heteroindanes: a new class of potent cannabimimetic ligands |
FR2831536A1 (fr) | 2001-10-26 | 2003-05-02 | Aventis Pharma Sa | Nouveaux derives de benzimidazoles, leur procede de preparation, leur application a titre de medicament, compositions pharmaceutiques et nouvelle utilisation notamment comme inhibiteurs de kdr |
AU2002334217B2 (en) | 2001-10-26 | 2008-07-03 | Aventis Pharmaceuticals Inc. | Benzimidazoles and analogues and their use as protein kinases inhibitors |
US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
AU2003225580A1 (en) | 2002-02-19 | 2003-09-09 | Pharmacia Corporation | Tricyclic pyrazole derivatives for the treatment of inflammation |
ES2281633T3 (es) | 2002-02-19 | 2007-10-01 | Pfizer Italia S.R.L. | Derivados triciclicos de pirazol, procedimiento para su preparacion y su uso como agentes antitumorales. |
WO2003097610A1 (en) | 2002-05-17 | 2003-11-27 | Pharmacia Italia S.P.A. | Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
US7429609B2 (en) | 2002-05-31 | 2008-09-30 | Eisai R & D Management Co., Ltd. | Pyrazole compound and medicinal composition containing the same |
US7449488B2 (en) | 2002-06-04 | 2008-11-11 | Schering Corporation | Pyrazolopyrimidines as protein kinase inhibitors |
CA2487211C (en) | 2002-06-04 | 2010-09-14 | Neogenesis Pharmaceuticals, Inc. | Pyrazolo(1,5a) pyrimidine compounds as antiviral agents |
US20050282733A1 (en) | 2002-06-27 | 2005-12-22 | Prins Johannes B | Differentiation modulating agents and uses therefor |
GB0218625D0 (en) | 2002-08-10 | 2002-09-18 | Astex Technology Ltd | Pharmaceutical compounds |
FR2845382A1 (fr) | 2002-10-02 | 2004-04-09 | Sanofi Synthelabo | Derives d'indazolecarboxamides, leur preparation et leur utilisation en therapeutique |
TWI325865B (en) | 2003-02-27 | 2010-06-11 | Palau Pharma Sa | Pyrazolopyridine derivatives |
US7135575B2 (en) | 2003-03-03 | 2006-11-14 | Array Biopharma, Inc. | P38 inhibitors and methods of use thereof |
EP1644371B1 (en) | 2003-07-03 | 2008-02-13 | Aventis Pharmaceuticals Inc. | Pyrazoloisoquinoline derivatives as kinase inhibitors |
GT200400136A (es) | 2003-07-30 | 2005-05-02 | Compuestos de indazol 3,5-disustituidos, composiciones farmaceuticas y metodos para intervenir en o inhibirlaproliferacion celular. | |
US7008953B2 (en) | 2003-07-30 | 2006-03-07 | Agouron Pharmaceuticals, Inc. | 3, 5 Disubstituted indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation |
US20050090529A1 (en) | 2003-07-31 | 2005-04-28 | Pfizer Inc | 3,5 Disubstituted indazole compounds with nitrogen-bearing 5-membered heterocycles, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation |
WO2005014554A1 (en) | 2003-08-08 | 2005-02-17 | Astex Therapeutics Limited | 1h-indazole-3-carboxamide compounds as mapkap kinase modulators |
US8969372B2 (en) | 2003-11-14 | 2015-03-03 | Aptose Boisciences Inc. | Aryl imidazoles and their use as anti-cancer agents |
EP1532980A1 (en) | 2003-11-24 | 2005-05-25 | Novo Nordisk A/S | N-heteroaryl indole carboxamides and analogues thereof, for use as glucokinase activators in the treatment of diabetes |
FR2864084B1 (fr) | 2003-12-17 | 2006-02-10 | Aventis Pharma Sa | Nouveaux derives organophosphores des indazoles et leur utilisation comme medicaments |
FR2867778B1 (fr) | 2004-03-16 | 2006-06-09 | Sanofi Synthelabo | Utilisation de derives d'indazolecarboxamides pour la preparation d'un medicament destine au traitement et a la prevention du paludisme |
US20050234095A1 (en) | 2004-03-25 | 2005-10-20 | Wenge Xie | Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof |
ATE487716T1 (de) | 2004-04-22 | 2010-11-15 | Memory Pharm Corp | Indole, 1h-indazole, 1,2-benzisoxazole, 1,2- benzoisothiazole, deren herstellung und verwendungen |
JP2007537296A (ja) | 2004-05-14 | 2007-12-20 | アボット・ラボラトリーズ | 治療薬としてのキナーゼ阻害薬 |
JP2008505167A (ja) | 2004-07-05 | 2008-02-21 | アステックス、セラピューティックス、リミテッド | 医薬組成物 |
EP2239262A3 (en) | 2004-07-27 | 2011-10-19 | SGX Pharmaceuticals, Inc. | Fused ring heterocycle kinase modulators |
US7626021B2 (en) | 2004-07-27 | 2009-12-01 | Sgx Pharmaceuticals, Inc. | Fused ring heterocycle kinase modulators |
AR050188A1 (es) | 2004-08-03 | 2006-10-04 | Uriach Y Compania S A J | Compuestos heterociclicos condensados utiles en terapia como inhibidores de quinasas p38 y composiciones farmaceuticas que los contienen |
WO2006024945A1 (en) | 2004-09-03 | 2006-03-09 | Pfizer Inc. | Pharmaceutical compositions comprising a cdk inhibitor |
US7652043B2 (en) | 2004-09-29 | 2010-01-26 | The Johns Hopkins University | WNT pathway antagonists |
WO2006054143A1 (en) | 2004-11-17 | 2006-05-26 | Pfizer Inc. | Polymorphs of {5-[3-(4,6-difluoro-1h-benzoimidazol-2-yl)-1h-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-amine |
US20060116519A1 (en) | 2004-11-17 | 2006-06-01 | Agouron Pharmaceuticals, Inc. | Synthesis of 5-bromo-4-methyl-pyridin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester |
WO2006063302A2 (en) | 2004-12-10 | 2006-06-15 | Wyeth | Variants of glycogen synthase kinase 3 and uses thereof |
US20060142247A1 (en) | 2004-12-17 | 2006-06-29 | Guy Georges | Tricyclic heterocycles |
EP2395000A1 (en) | 2004-12-30 | 2011-12-14 | Astex Therapeutics Limited | Benzimidazole compounds that modulate the activity of CDK, GSK and aurora kinases |
EP1861161A4 (en) | 2005-01-24 | 2012-05-16 | Neurosystec Corp | APPARATUS AND METHOD FOR DISPENSING THERAPEUTIC AND / OR OTHER AGENTS IN THE INTERNAL EAR AND OTHER FABRICS |
WO2006130673A1 (en) | 2005-05-31 | 2006-12-07 | Janssen Pharmaceutica, N.V. | 3-benzoimidazolyl-pyrazolopyridines useful in treating kinase disorders |
CN101243088B (zh) | 2005-08-25 | 2011-06-29 | 霍夫曼-拉罗奇有限公司 | p38 MAP激酶抑制剂及使用它的方法 |
US8106066B2 (en) | 2005-09-23 | 2012-01-31 | Memory Pharmaceuticals Corporation | Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof |
AR055669A1 (es) | 2005-10-03 | 2007-08-29 | Astrazeneca Ab | Derivados de 3h - imidazo[4, 5 -b]piridina como inhibidores selectivos de gsk3, metodos e internediarios para su preparacion, composiciones farmaceuticas que los contienen y su uso para la elaboracion de un medicamento para el tratamiento de enfermedades neurodegenerativas y mentales. |
TW200804338A (en) | 2005-11-24 | 2008-01-16 | Astrazeneca Ab | New compounds |
GB0602178D0 (en) | 2006-02-03 | 2006-03-15 | Merck Sharp & Dohme | Therapeutic treatment |
CN101400681A (zh) | 2006-03-23 | 2009-04-01 | 霍夫曼-拉罗奇有限公司 | 取代的吲唑衍生物,它们的制备和作为药剂的应用 |
EP2001480A4 (en) | 2006-03-31 | 2011-06-15 | Abbott Lab | Indazole CONNECTIONS |
JP2009541268A (ja) | 2006-06-22 | 2009-11-26 | ビオヴィトルム・アクチボラゲット(プブリクト) | Mnkキナーゼ阻害剤としてのピリジンおよびピラジン誘導体 |
WO2008061109A2 (en) | 2006-11-15 | 2008-05-22 | Forest Laboratories Holdings Limited | Indazole derivatives useful as melanin concentrating receptor ligands |
EP1932834B1 (en) | 2006-12-11 | 2011-04-27 | The Genetics Company, Inc. | Aromatic 1,4-DI-Carboxylamides and their use |
EP1932830A1 (en) | 2006-12-11 | 2008-06-18 | The Genetics Company, Inc. | Sulfonamides and their use as a medicament |
CA2672167C (en) | 2006-12-14 | 2016-01-26 | Bayer Schering Pharma Aktiengesellschaft | Dihydropyridine derivatives useful as protein kinase inhibitors |
EA200901157A1 (ru) | 2007-04-10 | 2010-04-30 | ЭсДжиИкс ФАРМАСЬЮТИКАЛЗ, ИНК. | Конденсированные кольцевые гетероциклические модуляторы киназы |
WO2008137408A1 (en) | 2007-04-30 | 2008-11-13 | Genentech, Inc. | Pyrazole inhibitors of wnt signaling |
US8129519B2 (en) | 2007-05-10 | 2012-03-06 | Cholody Wieslaw M | Derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine and uses thereof |
US20080287452A1 (en) | 2007-05-16 | 2008-11-20 | Wyeth | Heteroaryl/aryl pyrimidine analogs and their use as agonists of the wnt-beta-catenin cellular messaging system |
US8304408B2 (en) | 2007-05-24 | 2012-11-06 | The Regents Of The University Of California | Wnt signaling inhibitors, and methods for making and using them |
CL2008001540A1 (es) | 2007-05-29 | 2009-05-22 | Sgx Pharmaceuticals Inc | Compuestos derivados de pirrolopiridinas y pirazolopiridinas; composicion farmaceutica; y uso en el tratamiento del cancer. |
WO2008150845A1 (en) | 2007-05-31 | 2008-12-11 | Vanderbilt University | Screening for wnt pathway modulators and pyrvinium for the treatment of cance |
CN101790526A (zh) | 2007-06-08 | 2010-07-28 | 雅培制药有限公司 | 用作激酶抑制剂的5-杂芳基取代的吲唑化合物 |
US8648069B2 (en) | 2007-06-08 | 2014-02-11 | Abbvie Inc. | 5-substituted indazoles as kinase inhibitors |
US20110301155A1 (en) | 2007-06-19 | 2011-12-08 | Tsuneo Yasuma | Indazole compounds for activating glucokinase |
FR2917735B1 (fr) | 2007-06-21 | 2009-09-04 | Sanofi Aventis Sa | Nouveaux indazoles substitutes, leur preparation et leur utilisation en therapeutique |
WO2009011850A2 (en) | 2007-07-16 | 2009-01-22 | Abbott Laboratories | Novel therapeutic compounds |
US20100190736A1 (en) | 2007-08-02 | 2010-07-29 | Nerviano Medical Sciences S.R.L. | Morpholinyl anthracycline derivative combined with protein kinase inhibitors |
RU2350271C1 (ru) | 2007-08-20 | 2009-03-27 | Федеральное государственное учреждение "Российский научный центр "Восстановительная травматология и ортопедия" имени академика Г.А. Илизарова Федерального агентства по высокотехнологичной медицинской помощи", ФГУ "РНЦ "ВТО" им. акад. Г.А. Илизарова Росмедтехнологий" | Способ лечения ранних стадий остеоартроза тазобедренного сустава |
EP2185556A1 (en) | 2007-08-27 | 2010-05-19 | Wyeth a Corporation of the State of Delaware | Imidazopyridine analogs and their use as agonists of the wnt-beta-catenin cellular messaging system |
US9259399B2 (en) | 2007-11-07 | 2016-02-16 | Cornell University | Targeting CDK4 and CDK6 in cancer therapy |
EP2231662B1 (en) | 2007-12-19 | 2011-06-22 | Genentech, Inc. | 8-anilinoimidazopyridines and their use as anti-cancer and/or anti-inflammatory agents |
MX2010014394A (es) | 2008-06-20 | 2011-05-19 | Rottapharm Spa | Derivados de 6-1h-imidazo-quinazolina y quinolinas, nuevos inhibidores de monoamina oxidasa y ligandos del receptor de imidazolina. |
KR101061599B1 (ko) | 2008-12-05 | 2011-09-02 | 한국과학기술연구원 | 비정상 세포 성장 질환의 치료를 위한 단백질 키나아제 저해제인 신규 인다졸 유도체, 이의 약학적으로 허용가능한염 및 이를 유효성분으로 함유하는 약학적 조성물 |
CN101440092B (zh) | 2008-12-25 | 2010-11-17 | 浙江大学 | 2-吲唑-4-氮杂吲哚-5-氨基衍生物及制备和应用 |
JP2012520887A (ja) | 2009-03-18 | 2012-09-10 | シェーリング コーポレイション | ジアシルグリセロールアシルトランスフェラーゼの阻害剤としての二環式化合物 |
JP2012521429A (ja) | 2009-03-23 | 2012-09-13 | メルク・シャープ・エンド・ドーム・コーポレイション | 疼痛治療用のp2x3受容体アンタゴニスト |
EP3025724B1 (en) | 2009-05-13 | 2018-07-11 | The University of North Carolina At Chapel Hill | Cyclin dependent kinase inhibitors and methods of use |
SG177740A1 (en) | 2009-07-23 | 2012-02-28 | Univ Vanderbilt | Substituted benzoimidazolesulfonamides and substituted indolesulfonamides as mglur4 potentiators |
ES2556350T3 (es) | 2009-08-10 | 2016-01-15 | Samumed, Llc | Inhibidores de indazol de la vía de señalización de Wnt y sus usos terapéuticos |
CN102595899A (zh) | 2009-08-10 | 2012-07-18 | 埃皮瑟瑞克斯有限公司 | 作为wnt/b-联蛋白信号传导途径抑制剂的吲唑及其治疗用途 |
WO2011050245A1 (en) | 2009-10-23 | 2011-04-28 | Yangbo Feng | Bicyclic heteroaryls as kinase inhibitors |
NZ601376A (en) | 2009-12-21 | 2014-03-28 | Array Biopharma Inc | Substituted n-(1h-indazol-4-yl)imidazo[1, 2-a]pyridine-3- carboxamide compounds as cfms inhibitors |
CA2785037C (en) | 2009-12-21 | 2018-01-16 | Samumed, Llc | 1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
WO2011123890A1 (en) | 2010-04-06 | 2011-10-13 | Peter Maccallum Cancer Institute | Radioprotector compounds and methods |
DE102010043379A1 (de) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 6-Fluor-1H-Pyrazolo[4,3-b]pyridine und ihre Verwendung |
WO2012068589A2 (en) | 2010-11-19 | 2012-05-24 | Constellation Pharmaceuticals | Modulators of methyl modifying enzymes, compositions and uses thereof |
MX336966B (es) | 2011-01-13 | 2016-02-08 | Novartis Ag | Novedosos derivados y su uso en el tratamiento de transtornos neurologicos. |
US8889684B2 (en) | 2011-02-02 | 2014-11-18 | Boehringer Ingelheim International Gmbh | Azaindolylphenyl sulfonamides as serine/threonine kinase inhibitors |
US9464065B2 (en) | 2011-03-24 | 2016-10-11 | The Scripps Research Institute | Compounds and methods for inducing chondrogenesis |
JP2014509660A (ja) | 2011-04-01 | 2014-04-21 | ユニバーシティ・オブ・ユタ・リサーチ・ファウンデイション | PDK1キナーゼの阻害剤としての置換3−(1H−ベンゾ{d}イミダゾール−2−イル)−1H−インダゾール類似体 |
AU2012290116B2 (en) | 2011-08-02 | 2016-11-03 | Buck Institute For Research On Aging | Tropinol esters and related compounds to promote normal processing of APP |
CA2838784A1 (en) | 2011-08-12 | 2013-02-21 | F. Hoffmann-La Roche Ag | Pyrazolo[3,4-c]pyridine compounds and methods of use |
JP5855253B2 (ja) | 2011-08-12 | 2016-02-09 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | インダゾール化合物、組成物及び使用方法 |
JP6096778B2 (ja) | 2011-09-01 | 2017-03-15 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | ピロロピラジンキナーゼ阻害剤 |
KR102010611B1 (ko) | 2011-09-14 | 2019-08-13 | 사뮤메드, 엘엘씨 | 인다졸-3-카르복사미드 및 WNT/β-카테닌 신호생성 경로 저해제들로써의 이들 용도 |
EP2810198B1 (en) | 2012-01-30 | 2023-07-12 | Universiteit Gent | Anti-invasive compounds |
WO2013142817A2 (en) | 2012-03-23 | 2013-09-26 | Dennis Brown | Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo |
PH12017500997A1 (en) | 2012-04-04 | 2018-02-19 | Samumed Llc | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
US9056874B2 (en) | 2012-05-04 | 2015-06-16 | Novartis Ag | Complement pathway modulators and uses thereof |
PT2770994T (pt) | 2012-05-04 | 2019-11-04 | Samumed Llc | 1h-pirazolo[3,4-b]piridinas e utilizações terapêuticas destas |
EP2844651A1 (en) | 2012-05-04 | 2015-03-11 | Basf Se | Substituted pyrazole-containing compounds and their use as pesticides |
JP6355648B2 (ja) | 2013-01-08 | 2018-07-11 | サミュメッド リミテッド ライアビリティ カンパニー | Wntシグナル伝達経路の3−(ベンゾイミダゾール−2−イル)−インダゾール阻害剤およびそれらの治療的使用 |
US9327886B2 (en) * | 2013-03-13 | 2016-05-03 | Bayer Healthcare Llc | Vial container with collar cap |
ES2824723T3 (es) | 2013-03-14 | 2021-05-13 | Galapagos Nv | Nuevos compuestos y composiciones farmacéuticas de los mismos para el tratamiento de trastornos inflamatorios |
CA2942687A1 (en) | 2014-03-20 | 2015-09-24 | Samumed, Llc | 5-substituted indazole-3-carboxamides and preparation and use thereof |
WO2016040193A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
WO2016040184A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
US9538272B2 (en) | 2014-09-08 | 2017-01-03 | Apple Inc. | Acoustic mesh and methods of use for electronic devices |
WO2016040188A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
WO2016040180A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
WO2016040190A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
WO2016040182A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-1h-imidazo[4,5-c]pyridine and therapeutic uses thereof |
WO2016040185A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof |
WO2016040181A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
US10206909B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10285982B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10329309B2 (en) | 2015-08-03 | 2019-06-25 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10206908B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
WO2017024003A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
WO2017023987A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
WO2017023988A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10383861B2 (en) | 2015-08-03 | 2019-08-20 | Sammumed, LLC | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10392383B2 (en) | 2015-08-03 | 2019-08-27 | Samumed, Llc | 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US20180214428A1 (en) | 2015-08-03 | 2018-08-02 | Samumed, Llc | 3-(1h-indol-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US10285983B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-B] pyridines and therapeutic uses thereof |
WO2017023981A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[2,3-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
WO2017023972A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10604512B2 (en) | 2015-08-03 | 2020-03-31 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof |
WO2017024026A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-indol-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof |
WO2017024021A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
US20180228780A1 (en) | 2015-08-03 | 2018-08-16 | Samumed, Llc | 3-(1h-pyrrolo[2,3-c]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
US10463651B2 (en) | 2015-08-03 | 2019-11-05 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-indazoles and therapeutic uses thereof |
WO2017023993A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-indol-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
WO2017079759A1 (en) | 2015-11-06 | 2017-05-11 | Samumed, Llc | 2-(1h-indazol-3-yl)-3h-imidazo[4,5-c]pyridines and their anti-inflammatory uses thereof |
SG10201912248RA (en) | 2016-06-01 | 2020-02-27 | Samumed Llc | Process for preparing n-(5-(3-(7-(3-fluorophenyl)-3h-imidazo[4,5-c]pyridin-2-yl)-1h-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide |
MX2019004616A (es) | 2016-10-21 | 2019-11-21 | Samumed Llc | Métodos de uso de indazol-3-carboxamidas y su uso como inhibidores de la ruta de señalización de wnt/b-catenina. |
MA46696A (fr) | 2016-11-07 | 2019-09-11 | Samumed Llc | Formulations injectables à dose unique prêtes à l'emploi |
-
2017
- 2017-11-07 MA MA046696A patent/MA46696A/fr unknown
- 2017-11-07 WO PCT/US2017/060481 patent/WO2018085865A1/en unknown
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- 2017-11-07 KR KR1020197015685A patent/KR102558716B1/ko active IP Right Grant
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- 2017-11-07 EP EP17801245.6A patent/EP3534878A1/en active Pending
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US20210145807A1 (en) | 2021-05-20 |
EP3534878A1 (en) | 2019-09-11 |
JP2019533702A (ja) | 2019-11-21 |
MA46696A (fr) | 2019-09-11 |
US20180133199A1 (en) | 2018-05-17 |
WO2018085865A1 (en) | 2018-05-11 |
KR102558716B1 (ko) | 2023-07-21 |
US10758523B2 (en) | 2020-09-01 |
US20230139639A1 (en) | 2023-05-04 |
KR20190082834A (ko) | 2019-07-10 |
US11446288B2 (en) | 2022-09-20 |
US11819499B2 (en) | 2023-11-21 |
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