JP6130495B2 - カンナビノイド受容体活性関連障害及び疾患を調節する方法 - Google Patents
カンナビノイド受容体活性関連障害及び疾患を調節する方法 Download PDFInfo
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- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
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- 201000003120 testicular cancer Diseases 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229930185603 trichostatin Natural products 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
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- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
- 229940006486 zinc cation Drugs 0.000 description 1
- 108020001588 κ-opioid receptors Proteins 0.000 description 1
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
(Y1、Y2及びY3は独立に、水素、ハロゲン、SH、スルホキシド、スルホン、スルファンアミドを含めた硫黄含有部分並びに関連アルキル及び芳香族置換部分、低級−OR6及び−NR7R8であり、R6は、H又は低級アルキルであり、R7及びR8は独立に、水素、低級アルキル、アルコキシカルボニル、アシル又はアミノカルボニルである)である]を有し、化合物は光学活性である。
のうち1種である。
AKAP:A−キナーゼアンカリングタンパク質
AM251:1−(2,4−ジクロロフェニル)−5−(4−ヨードフェニル)−4−メチル−N−(1−ピペリジル)ピラゾール−3−カルボキサミド
AM630:1−[2−(モルホリン−4−イル)エチル]−2−メチル−3−(4−メトキシベンゾイル)−6−ヨードインドール
AR:アドレナリン受容体
BBB:血液脳関門
β2−AR:β2−アドレナリン受容体
CB:カンナビノイド
ERK:細胞外調節性キナーゼ
Fen:フェノテロール
GPR55:Gタンパク質共役型受容体55
GPCR:Gタンパク質共役型受容体
HPLC:高性能液体クロマトグラフィー
IAM−PC:固定化人工膜クロマトグラフィー支持体
ICI118,551:3−(イソプロピルアミノ)−1−[(7−メチル−4−インダニル)オキシ]ブタン−2−オール
ICYP:[125I]シアノピンドロール
IP:腹膜内
IV:静脈内
MNF:4−メトキシ−1−ナフチルフェノテロール
NF:ナフチルフェノテロール
OGTT:経口糖負荷試験
UV:紫外
1.約30kg/m2以上のBMIなどの肥満症;
2.高い空腹時血糖(FPG)レベル;
3.耐糖能異常(IGT);
4.非白人民族性;
5.高インスリン血症;
6.高トリグリセリド血症;
7.糖尿病の家族歴;
8.妊娠糖尿病の病歴;
9.セデンタリーライフスタイル;及び
10.ヒトでは、中年又は高齢者の状態(すなわち、40歳以上)。
[式中、R1〜R3は独立に、水素、アシル、アルコキシカルボニル、アミノカルボニル又はそれらの組合せであり、
R4は、H又は低級アルキルであり、
R5は、低級アルキル、
(式中、X及びYは独立に、水素、低級−OR6及び−NR7R8から選択され、
R6は、低級アルキル又はアシルであり、
R7及びR8は独立に、水素、低級アルキル、アルコキシカルボニル、アシル又はアミノカルボニルである)である]
を有する。
[式中、Y1、Y2及びY3は独立に、水素、ハロゲン、SH、スルホキシド、スルホン、スルファンアミドを含めた硫黄含有部分並びに関連アルキル及び芳香族置換部分、低級−OR6及び−NR7R8であり、R6は、各出現について独立に、低級アルキル及びアシルから選択され、R7及びR8は独立に、水素、低級アルキル、アルコキシカルボニル、アシル又はアミノカルボニル(カルバモイル)である]
によって表される。特定の化合物では、Y1、Y2及びY3のうち少なくとも1つは、−OCH3である。
[式中、R6は、メチル、エチル、プロピル若しくはイソプロピル又はアセチルなどのアシルなどの低級アルキルである]
によって表されるものを含む。
が挙げられる。
[式中、X及びYは独立に、H、低級アルキル−OR6及び−NR7R8から選択され、R6は、低級アルキルであり、R7及びR8は独立に、水素又は低級アルキルである]
である。
[式中、XはH、−OR6又は−NR7R8である]
を有する。例えば、R6は、メチルであり得、又はR7及びR8は、水素である。
を有する。
を表す。
[式中、X、Y1、Y2及びY3は独立に、水素、−OR6及び−NR7R8であり、R6は独立に、水素、低級アルキル、アシル、アルコキシカルボニル又はアミノカルボニルであり、R7及びR8は独立に、水素、低級アルキル、アルコキシカルボニル、アシル又はアミノカルボニルである]
であり、化合物は、光学活性である。
[式中、Xは、−OH又は−OCH3である]
である。
である。
[X及びR1〜R3は、上記のとおりである]
の化学構造を有する。
を有する。
[式中、X及びR1〜R3は、上記のとおりである]
を有する。
を有する。
[式中、X及びR1〜R3は、上記のとおりである]
を有する。
[式中、X及びR1〜R3は、上記のとおりである]
を有する。
材料及び方法
この実施例は、例2〜4に使用される材料及び方法を記載する。
カンナビノイド受容体活性に対するフェノテロール及びフェノテロール類似体の特性決定
この実施例は、フェノテロール及び開示されているフェノテロール類似体の、カンナビノイド受容体活性をモジュレートする能力を特性決定するために実施された一連の研究を記載する。
カンナビノイド受容体モジュレーションの特性決定
この実施例は、フェノテロール及び開示されているフェノテロール類似体のカンナビノイド受容体活性をモジュレートする能力をさらに特性決定するために実施された一連の研究を記載する。
MNFのin vitro代謝的安定性
この実施例は、ヒト及びラット肝臓ミクロソームでのMNFの代謝的安定性を記載する。
IV投与後のin vivo分布及びクリアランス
MNFの血漿及び脳組織濃度を決定するために、10mg/kgのMNFの単回IV用量の投与後に、雄のスプラーグ−ドーリーラットから得られた血漿及び脳組織サンプル中のMNF及びその代謝産物の濃度を決定した。アッセイは、Eclipse XDB−C18ガードカラム(4.6mm×12.5mm)及びAtlantis HILICカラム(150×2.1mm ID、5mm)を使用して実施した。移動相は、成分Aとして0.1%ギ酸及び成分Bとしてアセトニトリルを含有する水からなっていた。直線勾配は以下の通りに流した:1.0ml/分の流速で、0分間95%B;5分間60%B;6分間80%B;10分間95%B。総実施時間は、1サンプルあたり15分とした。分析物の同定及び定量化は、ポジティブエレクトロスプレーイオン化モードにおいてAPI−4000 LC−MS/MSを使用して達成し、多重反応モニタリング(MRM)及び以下のMRMトランジション:MNF(369−200);MNF−Gluc(545−200)を使用してデータを獲得した。
MNFは、中枢神経系機能に対して有意な負の効果を有さない
この実施例は、MNFが、中枢神経系機能に対して有意な負の効果を有さないことを実証する。
(R,R’)−MNF及び(R,R’)−4−メトキシフェノテロール(MF)は、肝臓、結腸及び肺癌細胞成長の強力な阻害剤である
この実施例は、(R,R’)−MNF及び(R,R’)−4−メトキシフェノテロール(MF)が、肝臓、結腸及び肺癌細胞成長の強力な阻害剤であることを実証する。
マウスにおけるラットC6神経膠腫異種移殖片モデルにおける(R,R’)−4−メトキシ−1−ナフチルフェノテロールの抗腫瘍活性
この実施例は、マウスにおけるラットC6神経膠腫異種移殖片モデルにおけるMNFの抗腫瘍活性を実証する。
MNFは、GPR55媒介性リガンド内部移行を標的とし、癌細胞運動を損なう
この実施例は、MNFが、GPR55媒介性リガンド内部移行を標的とし、癌細胞運動を損なうことを実証する。
CB受容体活性によって調節される腫瘍の治療
この実施例は、フェノテロール、フェノテロール類似体又はそれらの組合せを、膠芽腫又は肝細胞癌腫などの腫瘍と関連している1種又は複数の徴候又は症状を低減又は阻害するのに治療上有効な量で含む組成物を投与することによって、ヒト対象において腫瘍を治療するために使用され得る方法を記載する。特定の方法、投与量及び投与様式が提供されるが、当業者ならば、治療に実質的に影響を及ぼさずに、変法を行ってもよいということは理解するであろう。
(R,R’)−MNF又は(R,R’)−NF(又は両方)を含む開示されている組成物の、アジュバント療法としての使用
この実施例は、悪性星状細胞腫について治療されているヒト対象において腫瘍成長を低減、防止又は遅延するために使用され得る方法を記載する。
我々は以下を特許請求する。
[請求項1]
カンナビノイド(CB)受容体活性によって調節される障害又は疾患を治療する方法であって、
CB受容体活性によって調節される障害若しくは疾患を有するか、又はそれを発症する危険性がある対象に、CB受容体活性によって調節される障害又は疾患と関連している1種又は複数の症状を低減するのに有効な量の化合物を投与し、それによって、CB受容体活性によって調節される対象における障害又は疾患と関連している1種又は複数の症状を低減することを含み、前記化合物は、式
[化1]
[式中、R 1 〜R 3 は独立に、水素、アシル、アルコキシカルボニル、アミノカルボニル(カルバモイル)又はそれらの組合せであり、
R 4 は、H又は低級アルキルであり、
R 5 は、
[化2]
(式中、Y 1 、Y 2 及びY 3 は独立に、水素、低級−OR 6 及び−NR 7 R 8 であり、
R 6 は、H又は低級アルキルであり、
R 7 及びR 8 は独立に、水素、低級アルキル、アルコキシカルボニル、アシル又はアミノカルボニルである)である]
を有し、前記化合物は光学活性である、上記方法。
[請求項2]
投与することが、治療上有効な量の化合物を投与することを含み、前記化合物内のR 4 が、メチル、エチル、n−プロピル又はイソプロピル基である、請求項1に記載の方法。
[請求項3]
投与することが、治療上有効な量の化合物を投与することを含み、前記化合物内のR 4 が、メチル基である、請求項2に記載の方法。
[請求項4]
投与することが、治療上有効な量の化合物を投与することを含み、前記化合物内のR 6 が、メチル基である、請求項1から3までのいずれか一項に記載の方法。
[請求項5]
投与することが、治療上有効な量の化合物を投与することを含み、前記化合物内のR 5 が、以下の構造:
[化3]
のうち1種である、請求項1から3までのいずれか一項に記載の方法。
[請求項6]
投与することが、治療上有効な量の化合物を投与することを含み、前記化合物内のR 1 、R 2 及びR 3 が、水素である、請求項1から5までのいずれか一項に記載の方法。
[請求項7]
投与することが、治療上有効な量の(R,R’)−4’−メトキシ−1−ナフチルフェノテロール(MNF)、(R,S’)−MNF、(R,R’)−エチルMNF、(R,R’)−ナフチルフェノテロール(NF)、(R,R’)−エチルNF、(R,S’)−NF及び(R,R’)−4’−アミノ−1−ナフチルフェノテロール(アミノNF)、(R,R’)−4’−ヒドロキシ−1−ナフチルフェノテロール(ヒドロキシNF)又はそれらの組合せを投与することを含む、請求項1に記載の方法。
[請求項8]
投与することが、治療上有効な量のMNF、NF又はそれらの組合せを投与することを含む、請求項7に記載の方法。
[請求項9]
投与することが、治療上有効な量のMNFを投与することを含む、請求項7に記載の方法。
[請求項10]
治療上有効な量の化合物を投与する前に、CB受容体活性によって調節される障害若しくは疾患を有するか、又はそれを発症する危険性がある対象を選択することをさらに含む、請求項1から9までのいずれか一項に記載の方法。
[請求項11]
CB受容体活性によって調節される障害若しくは疾患を有するか、又はそれを発症する危険性がある対象を選択することが、対象から得られたサンプルにおいて、CB受容体活性又は発現(又は両方)を測定することを含み、CB受容体活性又は発現(又は両方)の存在が、対象が、CB受容体活性によって調節される障害若しくは疾患を有するか、又はそれを発症する危険性があることを示す、請求項10に記載の方法。
[請求項12]
CB活性によって調節される障害若しくは疾患を有するか、又はそれを発症する危険性がある対象を選択することが、治療上有効な量の化合物を投与する前に、β2−AR活性を標的とする治療に応答しない障害又は疾患を有する対象を選択することを含む、請求項10又は11に記載の方法。
[請求項13]
CB受容体を発現する腫瘍の治療において使用される、請求項1から12までのいずれか一項に記載の方法。
[請求項14]
障害又は疾患が、CB受容体を発現する原発性脳腫瘍、CB受容体を発現する星状細胞腫、CB受容体を発現する膠芽腫、CB受容体を発現する肝細胞癌腫、結腸癌、肝臓癌及び肺癌からなる群から選択される、請求項1から12までに記載の方法。
[請求項15]
疾患又は障害と関連している1種又は複数の徴候又は症状を阻害することが、腫瘍若しくは癌細胞成長(又は両方)などの細胞成長、腫瘍体積又はそれらの組合せを阻害することを含む、請求項1から14までのいずれか一項に記載の方法。
[請求項16]
前記CB受容体が、GPR55である、請求項1から15までのいずれか一項に記載の方法。
[請求項17]
化合物の投与の前に、それと一緒に、又はその後などに、さらなる治療薬を投与することをさらに含む、請求項1から16までのいずれか一項に記載の方法。
[請求項18]
前記さらなる治療薬が化学療法薬である、請求項17に記載の方法。
[請求項19]
治療上有効な量の化合物を投与することが、治療上有効な量の前記化合物を医薬上許容される担体とともに投与することを含む、請求項1から18までのいずれか一項に記載の方法。
[請求項20]
前記対象がヒトである、請求項1から19までのいずれか一項に記載の方法。
Claims (13)
- カンナビノイド(CB)受容体を発現する腫瘍を治療するための医薬組成物であって、
(R,R’)−4’−メトキシ−1−ナフチルフェノテロール(MNF)、(R,S’)−MNF、(R,R’)−エチルMNF、(R,R’)−ナフチルフェノテロール(NF)、(R,R’)−エチルNF、(R,S’)−NF及び(R,R’)−4’−アミノ−1−ナフチルフェノテロール(アミノNF)、(R,R’)−4’−ヒドロキシ−1−ナフチルフェノテロール(ヒドロキシNF)又はそれらの組合せからなる群から選択される化合物を含有し、前記化合物はCB受容体を発現する腫瘍と関連している1種又は複数の徴候又は症状を低減する、上記医薬組成物。 - MNF、(R,S’)−MNF、NF又はそれらの組合せを含有する、請求項1に記載の医薬組成物。
- MNF、(R,S’)−MNF又はそれらの組合せを含有する、請求項1に記載の医薬組成物。
- 対象がCB受容体を発現する腫瘍を有するか、又はそれを発症する危険性がある、請求項1から3までのいずれか一項に記載の医薬組成物。
- 請求項4に記載の医薬組成物であって、前記医薬組成物を投与する前に、対象から得られたサンプルにおいて、CB受容体活性又は発現(又は両方)が測定され、CB受容体活性又は発現(又は両方)の存在が、対象が、CB受容体を発現する腫瘍を有するか、又はそれを発症する危険性があることを示す、医薬組成物。
- 対象がβ2−AR活性を標的とする治療に応答しない障害又は疾患を有する、請求項4又は5に記載の医薬組成物。
- 対象の障害又は疾患が、CB受容体を発現する原発性脳腫瘍、CB受容体を発現する星状細胞腫、CB受容体を発現する膠芽腫、CB受容体を発現する肝細胞癌腫、結腸癌、肝臓癌、肺癌、乳癌、及び膵臓癌からなる群から選択される、請求項1から6までのいずれか一項に記載の医薬組成物。
- CB受容体を発現する腫瘍と関連している1種又は複数の徴候又は症状を低減することが、腫瘍若しくは癌細胞成長(又は両方)などの細胞成長、腫瘍体積又はそれらの組合せを低減することを含む、請求項1から7までのいずれか一項に記載の医薬組成物。
- 前記CB受容体が、GPR55である、請求項1から8までのいずれか一項に記載の医薬組成物。
- 前記化合物の投与の前に、それと一緒に、又はその後などに、さらなる治療薬が投与される、請求項1から9までのいずれか一項に記載の医薬組成物。
- 前記さらなる治療薬が化学療法薬である、請求項10に記載の医薬組成物。
- 前記化合物が医薬上許容される担体とともに投与される、請求項1から11までのいずれか一項に記載の医薬組成物。
- 前記対象がヒトである、請求項1から12までのいずれか一項に記載の医薬組成物。
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BR112018006633A2 (pt) * | 2015-09-30 | 2018-10-23 | Bird Rock Bio Inc | anticorpos que se ligam ao receptor canabinóide 1 (cb1) humano |
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US11487195B2 (en) | 2018-04-26 | 2022-11-01 | Wonder Vision Techno Laboratory Co., Ltd. | Dome screen, dome screen projection apparatus, and method for fabricating the same |
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WO2013177418A1 (en) | 2013-11-28 |
US20150157580A1 (en) | 2015-06-11 |
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CA2874655C (en) | 2020-11-03 |
JP2015519347A (ja) | 2015-07-09 |
US20190000781A1 (en) | 2019-01-03 |
EP2854855A1 (en) | 2015-04-08 |
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