WO2018074409A1 - 慢性骨髄性白血病を治療又は寛解するための医薬組成物 - Google Patents
慢性骨髄性白血病を治療又は寛解するための医薬組成物 Download PDFInfo
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- WO2018074409A1 WO2018074409A1 PCT/JP2017/037338 JP2017037338W WO2018074409A1 WO 2018074409 A1 WO2018074409 A1 WO 2018074409A1 JP 2017037338 W JP2017037338 W JP 2017037338W WO 2018074409 A1 WO2018074409 A1 WO 2018074409A1
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- pharmacologically acceptable
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- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 title claims abstract description 37
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Images
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention provides (2S) -2-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoylamino] -4-methylpentanoic acid or its pharmacologically acceptable as an active ingredient Salts and 4-[(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide or pharmacology thereof
- the present invention relates to a pharmaceutical composition for treating or ameliorating a patient with chronic myeloid leukemia, which contains a pharmaceutically acceptable salt.
- Chronic myelogenous leukemia is one of the blood tumors that develop when hematopoietic stem cells become tumors and a marked increase in white blood cells is observed.
- Gleevec (registered trademark) is used as a first-line drug in the treatment of chronic myelogenous leukemia (Non-patent Document 1).
- Gleevec is 4-[(4-methylpiperazin-1-yl) methyl] -N- [4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl) amino] phenyl] benzamide monomethane Sulfonate (generic name: imatinib mesylate) can be used as an active ingredient to selectively inhibit the activity of Bcr-Abl tyrosine kinase, which is associated with exacerbation of chronic myeloid leukemia.
- Bestatin (registered trademark) is an active ingredient of (2S) -2-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoylamino] -4-methylpentanoic acid (generic name: Ubenimex) It is known that it binds to aminopeptidase present on the surface of immunocompetent cells and exhibits an immune enhancing action in cancer patients. Bestatin is approved by the Japanese authorities for clinical use and applied for the extension of survival time in combination with a maintenance-enhancing therapeutic agent after induction of remission of adult acute non-lymphocytic leukemia (Non-patent Document 2). In addition, the present inventors have previously reported that elderly or terminal cancer patients can be treated or ameliorated by the administration of bestatin at a low dose (10 mg / day) (Patent Document 1).
- An object of the present invention is to provide a new treatment method for chronic myelogenous leukemia which is less economical and physically burdensome for the patient.
- the present inventors have been clinically applied in the indication of prolonging the survival period in combination with a maintenance-enhancing therapeutic agent after induction of remission of adult acute non-lymphocytic leukemia.
- the bestatin that had been used at a dose much lower than the normal dose (30-60 mg / body / day) and Gleevec that was used in the treatment of chronic myeloid leukemia was much higher than the normal dose (400-600 mg / body / day) It was found that co-administration at a low dose is effective in the treatment and remission of patients with chronic myelogenous leukemia.
- the present invention is based on these findings.
- the present invention is as follows.
- This figure shows the number of posterior myeloid cells, leukocytes, neutrophils, platelets, lymphocytes, and neutrophils in peripheral blood by low-dose combination therapy with Gleevec and Bestatin for patients with chronic myelogenous leukemia It is a graph which shows the change of ratio (N / L ratio) of a number and a lymphocyte number.
- the present invention provides (2S) -2-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoylamino] as an active ingredient for treating or ameliorating patients with chronic myelogenous leukemia.
- -4-methylpentanoic acid or a pharmaceutically acceptable salt thereof and 4-[(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3-[[4- (3-pyridinyl ) -2-pyrimidinyl] amino] phenyl] -benzamide or a pharmacologically acceptable salt thereof.
- (2S) -2-[(2S, 3R) -3-Amino-2-hydroxy-4-phenylbutanoylamino] -4-methylpentanoic acid is commonly referred to as ubenimex and is used for adult acute nonlymphocytic leukemia It is known that it can be used as an active ingredient of an antineoplastic agent that has the effect and effect of prolonging the survival period in combination with maintenance-enhanced chemotherapeutic agents after induction of complete remission.
- (2S) -2-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoylamino] -4-methylpentanoic acid is referred to as “Ubenimex”.
- ubenimex or a pharmacologically acceptable salt thereof may be produced based on a conventionally known general method, for example, not only chemically synthesized but also microorganisms (for example, , Produced as a culture fermentation product of Streptomyces olivoreticuli).
- a conventionally known general method for example, not only chemically synthesized but also microorganisms (for example, , Produced as a culture fermentation product of Streptomyces olivoreticuli).
- microorganisms for example, Produced as a culture fermentation product of Streptomyces olivoreticuli.
- commercially available products such as “bestatin (registered trademark)” can be used.
- Ubenimex is not in the form of a salt, but may be a salt with hydrochloric acid, sulfuric acid, phosphoric acid, etc. as pharmacologically acceptable.
- 4-[(4-Methyl-1-piperazinyl) methyl] -N- [4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide is a compound of chronic myeloid leukemia Anti-malignant for KIT (CD117) -positive gastrointestinal stromal tumor, Philadelphia chromosome-positive acute lymphoblastic leukemia, and FIP1L1-PDGFR ⁇ -positive hypereosinophilic syndrome or chronic eosinophilic leukemia It is known that it can be used as an active ingredient of a tumor agent.
- the pharmacologically acceptable salt thereof is not particularly limited, but the form of monomethanesulfonate is known and generally used.
- 4-[(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] Benzamide is described as “imatinib” and its monomethanesulfonate salt is described as “imatinib mesylate”.
- imatinib or a pharmacologically acceptable salt thereof is obtained by a conventionally known general method (for example, US Pat. No. 5,521,184, WO 03/066663, US Pat. No. 6,894,051). And those chemically synthesized according to Japanese Laid-open Patent Publication No., etc.).
- commercially available products such as “Gleevec (registered trademark)” (imatinib mesylate) can be used.
- the amount of ubenimex or a pharmacologically acceptable salt thereof and imatinib or a pharmacologically acceptable salt thereof contained in the pharmaceutical composition of the present invention is suitable for administering an amount within the following range to a patient.
- the amount of ubenimex or a pharmacologically acceptable salt thereof can be appropriately selected from the range of 1 to 20 mg, 1 to 10 mg, or 1 to 5 mg
- Imatinib or a pharmacologically acceptable salt thereof can be included in the pharmaceutical composition in an amount appropriately selected from the range of 1 to 200 mg, 1 to 100 mg, or 1 to 50 mg.
- the pharmaceutical composition of the present invention may contain 10 mg of ubenimex or a pharmacologically acceptable salt thereof and 100 mg of imatinib or a pharmacologically acceptable salt thereof.
- the pharmaceutical composition of the present invention is an excipient that is commonly used in the manufacture of a medicament together with ubenimex, which is an active ingredient, or a pharmacologically acceptable salt thereof, and imatinib, or a pharmacologically acceptable salt thereof.
- ubenimex which is an active ingredient, or a pharmacologically acceptable salt thereof, and imatinib, or a pharmacologically acceptable salt thereof.
- Oral or parenteral administration e.g.
- the dosage form can be suitable for intrarectal administration.
- the pharmaceutical composition of the present invention is a solution, emulsion, liposome preparation, injection, suspension, ointment, cream, transdermal absorption agent, transmucosal absorption agent, tablet, pill, capsule, powder. , Powder forms, granules, fine granules, syrups and the like, but are not limited thereto. Each of these can be prepared, molded or prepared according to a method commonly used in the art.
- the pharmaceutical composition of the present invention is lyophilized to make it easy to store, and after use, dissolved in a diluent such as water, saline, buffer solution, etc., and adjusted to an appropriate concentration. It can also be used.
- a diluent such as water, saline, buffer solution, etc.
- the pharmaceutical composition of the present invention may be in the form of a combination containing both active ingredient ubenimex or a pharmacologically acceptable salt thereof and imatinib or a pharmacologically acceptable salt thereof, or Ubenimex, which is an active ingredient, or a pharmacologically acceptable salt thereof, and imatinib, or a pharmacologically acceptable salt thereof, in the form of a kit formulation contained in a single package suitable for combined administration. Also good.
- the “concurrent administration” includes not only the simultaneous administration of ubenimex or a pharmacologically acceptable salt thereof and imatinib or a pharmacologically acceptable salt thereof, but also ubenimex or a pharmacologically thereof.
- an acceptable salt and imatinib or a pharmacologically acceptable salt thereof are administered at intervals within a range where each active ingredient can act simultaneously.
- the administration route and administration means of ubenimex or a pharmacologically acceptable salt thereof and imatinib or a pharmacologically acceptable salt thereof may be the same or different. Also good.
- the pharmaceutical composition of the present invention can be administered to patients with chronic myelogenous leukemia for the purpose of treatment or remission of chronic myelogenous leukemia.
- Chronic myelogenous leukemia may be in any stage of chronic, transitional, and acute stages, and is not particularly limited.
- the patient with chronic myelogenous leukemia to be administered with the pharmaceutical composition of the present invention is preferably a patient whose urine pH value is neutral to alkaline.
- the pH value of urine can be confirmed as an index. Therefore, patients with chronic myelogenous leukemia for whom the pharmaceutical composition of the present invention is to be administered are patients whose urine pH value is neutral to alkaline.
- the patient is a mammal, including a human, preferably a human.
- the urine pH value of a cancer patient may be on the acidic side.
- the urine pH value is adjusted to neutral to alkaline by ingesting or administering one or more of the following substances (that is, improving the constitution) can do.
- the following substances include yellow-green vegetables, edible baking soda, alkalizing therapy (potassium citrate / sodium citrate hydrate combination agent (Uralit (registered trademark))) and the like.
- alkalizing therapy potassium citrate / sodium citrate hydrate combination agent (Uralit (registered trademark))
- the pH value of urine can be adjusted to neutral to alkaline. It is preferable to continuously improve the constitution until the pH value of the patient urine is adjusted to neutral to alkaline.
- the dose and frequency of administration of the pharmaceutical composition of the present invention to patients with chronic myelogenous leukemia may vary depending on factors such as the age, weight, and severity of the disease, but Ubenimex or its drug as an active ingredient
- the amount of salt that is physically acceptable is 1-20 mg / body / day, 1-10 mg / body / day, 5-15 mg / body / day, etc., or a total daily dose of 5-20 mg, 7- In an amount appropriately selected from 15 mg, 8-13 mg, 10 mg, and the like, and in the amount of imatinib as an active ingredient or a pharmacologically acceptable salt thereof, 1-200 mg / body / day, 1-100 mg / body / Day, 50-150 mg / body / day, etc., or total daily dose 50-200 mg, 70-150 mg, 80-130 m
- the amount is appropriately selected from, such as 100 mg, 1 ⁇ 3 times a day, can be administered every day or 1 to 21 days.
- the pharmaceutical composition of the present invention is administered to a patient once daily at a dose of 10 mg of ubenimex or a pharmacologically acceptable salt thereof and imatinib or a pharmacologically acceptable salt thereof at 100 mg.
- a dose of 10 mg of ubenimex or a pharmacologically acceptable salt thereof and imatinib or a pharmacologically acceptable salt thereof at 100 mg is administered to a patient once daily at a dose of 10 mg of ubenimex or a pharmacologically acceptable salt thereof and imatinib or a pharmacologically acceptable salt thereof at 100 mg.
- Non-patent Document 2 ubenimex is used at a dose of 30 mg once a day in combination with a chemotherapeutic agent for the purpose of enhancing maintenance after induction of complete remission of adult acute non-lymphocytic leukemia.
- imatinib or a pharmacologically acceptable salt thereof is usually used at a dose of 400 mg to 600 mg once a day, or 800 mg (400 mg twice a day) for patients with chronic myelogenous leukemia. (Non-Patent Document 1).
- ubenimex or a pharmacologically acceptable salt thereof and imatinib or a pharmacologically acceptable salt thereof are both conventionally used for patients with chronic myeloid leukemia. It can be used at much lower doses compared to the doses that have been provided.
- the effect of the pharmaceutical composition of the present invention is that one or more of the following (i) to (vii) is applied to a patient who has not been administered the pharmaceutical composition or who has received the pharmaceutical composition compared to a patient before administration: It can be evaluated using as an index.
- the number of rear bone marrow cells in the peripheral blood is reduced or eliminated.
- the white blood cell count in the peripheral blood is reduced.
- the number of neutrophils in peripheral blood is decreased.
- the number of platelets in peripheral blood is reduced.
- the ratio (NLR) of the neutrophil count (N) and lymphocyte count (L) in peripheral blood is decreased.
- the ratio (PLR) of the number of platelets (P) and the number of lymphocytes (L) in peripheral blood is decreased.
- Prolongation of survival period (life extension effect) is observed.
- the pharmaceutical composition of the present invention can be administered together with an existing therapeutic agent for chronic myeloid leukemia as necessary.
- therapeutic agents include dasatinib (trade name: Sprisel (registered trademark)), bosutinib (trade name: Boschlif (registered trademark)), nilotinib (trade name: tagcina (registered trademark)), and the like. These are not limited.
- the present invention further relates to a method for treating or ameliorating a patient with chronic myelogenous leukemia using the pharmaceutical composition of the present invention.
- Patients with chronic myelogenous leukemia that can be treated or ameliorated by this method, and the usage and dosage of the pharmaceutical composition of the present invention are as described above.
- Example 1 Low-dose and combined administration of Gleevec and Bestatin To a 71-year-old female chronic myeloid leukemia patient who had been administered Tasigna (registered trademark) (Nilotinib) since January 9, 2014, but had strong side effects The medication was discontinued after 5 days.
- Tasigna registered trademark
- FIG. 1 the disappearance of posterior myelocytes in the peripheral blood of patients associated with chronic myeloid leukemia was observed. It was also observed that the number of white blood cells, neutrophils, platelets, and the ratio of neutrophils to lymphocytes (N / L ratio) in the patient's peripheral blood were all significantly reduced.
- Tasigna (Nilotinib) was developed as a therapeutic agent for the transitional phase of chronic myelogenous leukemia from the chronic phase to the acute phase. There wasn't. On the other hand, it is known that Gleevec is not sufficiently effective against chronic myeloid leukemia in the transitional stage / acute stage.
- low-dose Gleevec together with low-dose bestatin combined with low-dose bestatin can result in chronic myelogenous leukemia (more specifically chronic bone marrow that is not in a chronic phase where Gleevec does not provide sufficient treatment) Treatment leukemia) and improvement of the patient's condition.
- the urine pH of the patient before the constitution improvement prescription was acidic (pH is less than 7), but the urine pH of the patient after the constitution improvement prescription was neutral to alkaline (7.0 to 7). .5).
- the present invention provides a low-dose combination therapy of Gleevec and Bestatin for patients with chronic myelogenous leukemia, and is useful in the medical industry because it can improve the patient's condition while reducing the burden on the patient. .
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Abstract
Description
(i)末梢血中の後骨髄球数が低下又は消失していること。
(ii)末梢血中の白血球数が低下していること。
(iii)末梢血中の好中球数が低下していること。
(iv)末梢血中の血小板数が低下していること。
(v)末梢血中の好中球数(N)とリンパ球数(L)の比(NLR)が低下していること。
(vi)末梢血中の血小板数(P)とリンパ球数(L)の比(PLR)が低下していること。
(vii)生存期間の延長(延命効果)が認められること。
実施例1:グリベック及びベスタチンの低用量・併用投与
71歳の女性の慢性骨髄性白血病患者に対し、2014年1月9日よりタシグナ(登録商標)(ニロチニブ)を投与していたが強い副作用が認められたため、5日間で投薬は中止された。
Claims (7)
- 有効成分として、(2S)-2-[(2S,3R)-3-アミノ-2-ヒドロキシ-4-フェニルブタノイルアミノ]-4-メチルペンタン酸又はその薬理学的に許容される塩、ならびに、4-[(4-メチル-1-ピペラジニル)メチル]-N-[4-メチル-3-[[4-(3-ピリジニル)-2-ピリミジニル]アミノ]フェニル]-ベンズアミド又はその薬理学的に許容される塩を含有する、慢性骨髄性白血病の患者を治療又は寛解するための医薬組成物。
- 1日あたり5~20mgの(2S)-2-[(2S,3R)-3-アミノ-2-ヒドロキシ-4-フェニルブタノイルアミノ]-4-メチルペンタン酸又はその薬理学的に許容される塩、及び1日あたり50~200mgの4-[(4-メチル-1-ピペラジニル)メチル]-N-[4-メチル-3-[[4-(3-ピリジニル)-2-ピリミジニル]アミノ]フェニル]-ベンズアミド又はその薬理学的に許容される塩が1日1~3回投与されるように用いられることを特徴とする、請求項1に記載の医薬組成物。
- 1日あたり10mgの(2S)-2-[(2S,3R)-3-アミノ-2-ヒドロキシ-4-フェニルブタノイルアミノ]-4-メチルペンタン酸又はその薬理学的に許容される塩、及び1日あたり100mgの4-[(4-メチル-1-ピペラジニル)メチル]-N-[4-メチル-3-[[4-(3-ピリジニル)-2-ピリミジニル]アミノ]フェニル]-ベンズアミド又はその薬理学的に許容される塩が1日1~3回投与されるように用いられることを特徴とする、請求項1または2に記載の医薬組成物。
- 前記投与が、経口投与である、請求項2または3に記載の医薬組成物。
- 前記患者の尿のpH値が中性からアルカリ性の範囲にある、請求項1~4のいずれか一項に記載の医薬組成物。
- 前記2つの有効成分が配合剤の形態で含まれる、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記2つの有効成分がキット製剤の形態で含まれる、請求項1~5のいずれか一項に記載の医薬組成物。
Priority Applications (6)
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US16/342,429 US20190247338A1 (en) | 2016-10-17 | 2017-10-16 | Pharmaceutical composition for treatment or remission of chronic myelogenous leukemia |
CN201780062328.8A CN109803659A (zh) | 2016-10-17 | 2017-10-16 | 用于治疗或缓解慢性髓性白血病的药物组合物 |
JP2018546319A JP6691971B2 (ja) | 2016-10-17 | 2017-10-16 | 慢性骨髄性白血病を治療又は寛解するための医薬組成物 |
KR1020197009443A KR102199253B1 (ko) | 2016-10-17 | 2017-10-16 | 만성 골수성 백혈병을 치료 또는 관해하기 위한 의약 조성물 |
EP17861731.2A EP3527211B1 (en) | 2016-10-17 | 2017-10-16 | Pharmaceutical composition for treatment or remission of chronic myelogenous leukemia |
US16/684,091 US11185517B2 (en) | 2016-10-17 | 2019-11-14 | Pharmaceutical composition for treatment or remission of chronic myelogenous leukemia |
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JP2016203662 | 2016-10-17 |
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US16/342,429 A-371-Of-International US20190247338A1 (en) | 2016-10-17 | 2017-10-16 | Pharmaceutical composition for treatment or remission of chronic myelogenous leukemia |
US16/684,091 Continuation US11185517B2 (en) | 2016-10-17 | 2019-11-14 | Pharmaceutical composition for treatment or remission of chronic myelogenous leukemia |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5521184A (en) | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
WO2003066613A1 (en) | 2002-02-07 | 2003-08-14 | Novartis Ag | N-phenyl-2-pyrimidine-amine derivatives |
US6894051B1 (en) | 1997-07-18 | 2005-05-17 | Novartis Ag | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
WO2016098546A1 (ja) | 2014-12-17 | 2016-06-23 | Delta-Fly Pharma株式会社 | 高齢又は末期の癌患者を治療又は寛解するための医薬組成物 |
JP2016203662A (ja) | 2015-04-15 | 2016-12-08 | カルソニックカンセイ株式会社 | 車両用照明装置およびカップホルダ |
-
2017
- 2017-10-16 KR KR1020197009443A patent/KR102199253B1/ko active IP Right Grant
- 2017-10-16 JP JP2018546319A patent/JP6691971B2/ja active Active
- 2017-10-16 CN CN201780062328.8A patent/CN109803659A/zh active Pending
- 2017-10-16 EP EP17861731.2A patent/EP3527211B1/en active Active
- 2017-10-16 TW TW106135262A patent/TWI674094B/zh active
- 2017-10-16 US US16/342,429 patent/US20190247338A1/en not_active Abandoned
- 2017-10-16 WO PCT/JP2017/037338 patent/WO2018074409A1/ja active Application Filing
-
2019
- 2019-11-14 US US16/684,091 patent/US11185517B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5521184A (en) | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
US6894051B1 (en) | 1997-07-18 | 2005-05-17 | Novartis Ag | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
WO2003066613A1 (en) | 2002-02-07 | 2003-08-14 | Novartis Ag | N-phenyl-2-pyrimidine-amine derivatives |
WO2016098546A1 (ja) | 2014-12-17 | 2016-06-23 | Delta-Fly Pharma株式会社 | 高齢又は末期の癌患者を治療又は寛解するための医薬組成物 |
JP2016203662A (ja) | 2015-04-15 | 2016-12-08 | カルソニックカンセイ株式会社 | 車両用照明装置およびカップホルダ |
Non-Patent Citations (9)
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EP3527211A4 (en) | 2020-09-23 |
CN109803659A (zh) | 2019-05-24 |
JP6691971B2 (ja) | 2020-05-13 |
KR102199253B1 (ko) | 2021-01-06 |
KR20190046937A (ko) | 2019-05-07 |
JPWO2018074409A1 (ja) | 2019-06-24 |
TWI674094B (zh) | 2019-10-11 |
US11185517B2 (en) | 2021-11-30 |
US20190247338A1 (en) | 2019-08-15 |
TW201817420A (zh) | 2018-05-16 |
US20200078322A1 (en) | 2020-03-12 |
EP3527211B1 (en) | 2023-08-23 |
EP3527211A1 (en) | 2019-08-21 |
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